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Chiziq signalizatsiya yo'lida Fringe nima faollashtirmoqda?

Chiziq signalizatsiya yo'lida Fringe nima faollashtirmoqda?


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KEGG -dan odamda signalizatsiya yo'lini ko'rib chiqing:
https://www.genome.jp/kegg-bin/show_pathway?hsa04330
Men Fringe nima faollashayotganini bilmoqchiman. Bu boshqa gen yoki oqsilga emas, balki o'zaro ta'sirga ishora qiladi. U nimani anglatadi?


Odatda, tur tasvirlangan reaksiyaga yoki o'zaro ta'sirga ishora qilganda, o'qlar turning bu reaktsiyaga ta'sirini bildiradi (masalan, ferment bilan kataliz). Oddiy o'q boshlari ijobiy ta'sirni (reaktsiyani kuchaytiruvchi, masalan, ferment), yassi boshlar esa salbiy ta'sirni (repressiyani) bildiradi. Bir molekuladan ikkinchisiga o'q konversiyani tasvirlash uchun ishlatilishi mumkin (masalan, glyukozaning glyukoza 6 fosfatiga aylanishi).

Yo'lni qanday tasvirlash bo'yicha haqiqiy standartlar yo'q. Shunday qilib, bu chalkash bo'lishi mumkin.

Bunday holda, Fringe aslida Notch signalini o'zgartiradi (pastga qarang). Shunday qilib, o'q mantiqiy. Biroq, rasmda Deltadan Notchgacha bo'lgan o'q ham bor, uni Delta Notchga aylantirilishi deb talqin qilish mumkin. Ular, shuningdek, Notch dan NICD ga o'qni ko'rsatadi, bu aslida konversiyani anglatadi. Men bu raqamdagi tasvirlar bir-biriga mos kelmasligini aytaman.

NCBI Gene Fringe inson gomologi haqidagi yozuvdan, LFNG:

Bu gen glikosiltransferaza 31 genlar oilasiga mansub. MFNG (GeneID: 4242) va RFNG (GeneID: 5986) genlarini o'z ichiga olgan ushbu genlar oilasining a'zolari, embrional rivojlanish davrida chegaralarni aniqlash uchun Notch signalizatsiya yo'lida harakat qiladigan, evolyutsion saqlanib qolgan glikosiltransferazalarni kodlaydi. Ularning genomik tuzilishi boshqa glikosiltransferalardan farq qilsa-da, bu oqsillar fukozaga xos beta-1,3-N-atsetilglukosaminiltransferaza faolligiga ega, bu esa Notchda O bilan bog'langan fukoza qoldiqlarining cho'zilishiga olib keladi. bu Notch signalini o'zgartiradi. Ushbu gen tomonidan kodlangan protein bir martalik II tipdagi Golji membranasi oqsili bo'lishi taxmin qilinmoqda, ammo u sichqoncha va Drosophila (PMID: 9187150)dagi tegishli oqsillar kabi ajralib chiqishi va proteolitik tarzda qayta ishlanishi mumkin. Bu gen mutatsiyalari autosomal retsessiv spondilokostal disostoz 3 bilan bog'liq. [RefSeq tomonidan taqdim etilgan, 2018 yil may]

Shao va boshqalardan (2002):

So'nggi tadqiqotlar shuni ko'rsatdiki, O-fukoza modifikatsiyalari Notch funktsiyasida muhim rol o'ynaydi. RNAi (11) yordamida sichqonlarda RNAi (11) yordamida O-fukosiltransferaza ekspressiyasini pasayishi notchga o'xshash fenotiplarni keltirib chiqaradi, bu esa Notch funktsiyasi uchun O-fukoza modifikatsiyalari zarurligini ko'rsatadi. Bundan tashqari, biz va boshqalar Notch faollashuvi fukozaga xos b1,3-N-asetilglyukozaminiltransferaza Fringe bilan Notchdagi O-fukoza kengayishi bilan modulyatsiyalanganligini ko'rsatdik (so'nggi sharhlar uchun 12 va 13-sonli sharhlarga qarang). Fringe birinchi marta Drosophila'da aniqlangan va Notchning Serratga javob berish qobiliyatini inhibe qilgani, lekin Deltaga javob berish qobiliyatini kuchaytirishi ko'rsatilgan (14). Sutemizuvchilardan uchta Drosophila Fringe gomologi aniqlandi: Lunatic fringe (Lfng), Manic fringe (Mfng) va Radical Fringe (Rfng) (15). Fringe oqsillarining beta-1,3-N-asetilglukosaminiltransferaza faolligi ularning Drosophila (16-18) va hujayra asosidagi Notch signalli tahlillarida (19) biologik faolligi uchun muhim ahamiyatga ega va Fringe Notch modulyatsiyasi uchun O-fukoza qoldiqlari zarur. faoliyat (16, 19). Shunday qilib, Fringe O-fukoza qismlariga GlcNAc qo'shilishi bilan Notch signalizatsiyasiga ta'sirini vositachilik qiladi. Shunga qaramay, Notch funktsiyasida O-fukozaning o'ziga xos roli ham, shakar tuzilishidagi o'zgarish Notch funktsiyasini qanday o'zgartirish mexanizmi ham ma'lum emas.


Hujayradagi chegaralarva rivojlanish biologiyasi

Tahrirchi va sharhlovchilarning aloqalari Loop tadqiqot profilidagi so'nggi ma'lumotlar bo'lib, ko'rib chiqish vaqtida ularning holatini aks ettirmasligi mumkin.


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    ULOSING

    T-hujayra gomeostazasi va differentsiatsiyasida tishli signalizatsiya

    Evolyutsion tarzda saqlanib qolgan Notch signalizatsiya yo'li etuk T-limfotsitlarning differentsiatsiyasi va funktsiyasini tartibga soladi, bu esa xost himoyasi, autoimmunitet va alloimmunitetda kontekstga bog'liq bo'lgan asosiy oqibatlarga olib keladi. T-hujayra reaktsiyalarida Notch signalizatsiyasining paydo bo'ladigan ta'siri T-hujayra rivojlanishida Notchning aniqlangan roliga asoslanadi. Bu erda biz hozirgacha o'rganilgan narsalarni tushunish va fiziologik ma'lumot to'plashda eng foydali bo'lgan eksperimental strategiyalarni ajratib ko'rsatish uchun o'sib borayotgan adabiyotni tanqidiy ko'rib chiqamiz. Biz etuk T hujayralarida Notch signalizatsiyasining funktsional oqibatlarini, shuningdek, asosiy maxsus Notch ligand-retseptorlari o'zaro ta'siri va quyi oqim molekulyar signalizatsiya yo'llarini tasvirlaymiz. Bizning maqsadimiz - bu kengaytiriladigan ishlar to'plamining kelajakdagi yo'nalishlarini va muhim ochiq savollarga javob berishning eng yaxshi usullarini aniqlashtirishga yordam berish.

    1.Kirish

    Notch, evolyutsion tarzda saqlanib qolgan hujayralararo signalizatsiya yo'li, tug'ma va moslashuvchan immunitet hujayralari rivojlanishining tanlangan bosqichlarida, shuningdek, etuk immunitet hujayralari funktsiyasini tartibga solishda ko'p funktsiyalarni bajaradi. Ham rivojlanayotgan, ham etuk immun hujayralarida ishtirok etib, Notch uy egasi mudofaasi va immun patologiyasining muhim aktyori sifatida namoyon bo'ladi.

    Notch birinchi bo'lib T hujayrali leykemiyadagi onkogen roli [1,2], T hujayralari rivojlanishidagi rolining buzilishi [3,4] asosida gematopoezga ta'sir qilish uchun kashf etilgan. Shu bilan birga, gomeostaz paytida etuk T hujayralarida Notch signalizatsiyasining paydo bo'layotgan roli va periferik to'qimalarda immunitet reaktsiyalari paydo bo'ldi. Hujayra tipidagi va kontekstga xos Notch signalizatsiyasi T-hujayrali immunitet reaktsiyalarini qanday shakllantirishi, shu bilan birga T-hujayrali patologiyalarni qo'zg'atish bo'yicha ishlar boshlandi.

    Bu erda biz oldingi ishlarni umumlashtirish va Notchning periferiyadagi etuk T hujayralariga qanday ta'sir qilishiga oid mavjud dalillarni tortish uchun adabiyotlarni ko'rib chiqamiz. Xususan, biz muhimligini muhokama qilamiz in vivo, funktsiyalarni yo'qotish strategiyasi, aksincha, eng ishonchli isbotlangan in vitro va funktsiyani oshirish bo'yicha tajribalar. Umuman olganda, biz ushbu sohada yaratilgan narsalarning aniq tasvirini taqdim etishni va Notchning etuk T hujayralarida qanday ishlashi uchun kattaroq mavzularni aniqlashni maqsad qilganmiz.

    2. Notch signalizatsiyasi haqida umumiy ma'lumot

    Notch - bu yujaktrin Notch ligand -retseptorlari o'zaro ta'siri orqali boshqariladigan hujayra -hujayra aloqasining yuqori darajada saqlanib qolgan yo'lidir (1 -rasm). To'rtta sutemizuvchi heterodimerik Notch retseptorlari paralellari (Notch1-4) Jagged (Jag1 va Jag2) va Delta (Dll1, Dll3 va Dll4) oilalaridagi beshta Notch ligandlaridan biri bilan o'zaro ta'sir qiladi [5,6]. Notch ligandlari Notch signalizatsiyasini faollashtiradi, Dll3 bundan mustasno, bu yo'lning tabiiy antagonisti [5]. Ligand -retseptorlari o'zaro ta'siridan kelib chiqadigan mexanik kuch Notch retseptorida ketma -ket proteolitik bo'linishlarni keltirib chiqaradi. Birinchidan, ADAM oilasi metalloproteazasi (ADAM10) retseptorning membrana-proksimal hujayradan tashqari domenini nishonga olib, uni g-sekretaz kompleksiga sezgir qiladi, bu esa intramembran proteolizini qo'zg'atadi va hujayra ichidagi Notch (ICN) ni sitoplazmaga chiqaradi. Yadroga ko'chib o'tgandan so'ng, ICN DNKni bog'lovchi transkripsiya omili RBP-Jk bilan o'zaro ta'sir qiladi va Mastermind-ga o'xshash oilaning (MAML1-3) transkripsiyaviy ko-aktivatorini jalb qiladi [5-9]. O'z navbatida MAML boshqa transkripsiya aktivatorlari, jumladan, xromatinni o'zgartiruvchi fermentlar, masalan, histon asetiltransferazalari va transkripsiyani faollashtirish mexanizmining boshqa komponentlari bilan o'zaro ta'sir qiladi.

    Shakl 1. Notch signalizatsiyasiga umumiy nuqtai. Yetuk T hujayralari bilan ifodalangan sutemizuvchilar Notch retseptorlari qo'shni hujayralarda (ikkilamchi limfoid organlardagi stromal hujayralar yoki professional antijen ko'rsatuvchi hujayralar) ifodalangan to'rtta faollashtiruvchi liganddan (Jagged 1/2 yoki Delta o'xshash 1/4) juxtacrine signallarini oladi. Ligand/retseptorlar bilan bog‘lanishi birinchi navbatda ADAM10 metalloproteaza, so‘ngra g-sekretaz kompleksi tomonidan Notch retseptorining ketma-ket proteolitik bo‘linishini keltirib chiqaradi. Ushbu bo'linishlar hujayra ichidagi Notch (ICN) ni sitoplazmaga chiqaradi, u erda DNK bilan bog'lovchi transkripsiya omili RBP-Jk va Mastermind-ga o'xshash (MAML) oilasining a'zosi bo'lgan transkripsiya faollashuv kompleksini hosil qilish uchun yadroga kiradi va bu o'z navbatida qo'shimcha moddalarni jalb qiladi. transkripsiya koaktivatorlari (CoA). Notch transkripsiya kompleksi xromatin tuzilishini kuchaytiruvchi va promotorlar klasterlarini hosil qilish uchun o'zgartiradi va transkripsiyaga ta'sir qiladi. Ba'zi hollarda, ICN kanonik bo'lmagan RBP-Jκ/MAML-dan mustaqil yo'llar orqali signal bergani haqida xabar berilgan.

    Notch signalizatsiyasi orqali transkripsiya regulyatsiyasi bir qancha kontekstlarda o'rganilgan bo'lsa-da, Notch-qo'zg'atilgan saraton kasalliklari (masalan, T-hujayrali o'tkir limfoblastik leykemiya, B-hujayrali limfoproliferativ kasalliklar, ko'krak saratoni) haqidagi ma'lumotlar hozirgi kunga qadar eng batafsil ma'lumotlarni taqdim etdi. T-hujayrali leykemiyada ICN/RBP-Jk komplekslari genomdagi minglab saytlarni bog'laydi, garchi 10% dan kamrog'i aslida Notch signalining blokadasi bilan dinamik ravishda tartibga solinadi. Dinamik tartibga solingan ushbu saytlarning ko'pchiligi Notch bandligi xromatin regulyatsiyasining o'zgarishi bilan bog'liq bo'lgan masofaviy kuchaytirgichlar bilan birlashtirilgan [10]. Qizig'i shundaki, yaqinda o'tkazilgan ishlar onkogen Notchning xromatin aylanishiga ta'sir ko'rsatuvchi vositalarni "3D kliklari" ga ta'sir o'tkazuvchi kuchaytiruvchi/targ'ibotchi fazoviy klasterlarning joylashishiga qanday ta'sir qilishi mumkinligini yoritib berdi (1 -rasm) [11]. Faoliyatning bu shakli maqsadli genlarning statik kogortasiga ta'siridan tashqari, gen ekspresiyasini Notch vositachiligida boshqarish mexanizmlarini kengaytiradi, bu shuni ko'rsatadiki, boshqa signallarning konteksti kuchaytirgichning faollashuvi va xromatinning joylashishini aniqlash uchun muhim bo'lishi mumkin. Shunday qilib, individual Notch maqsadli genlar kontekstga juda bog'liq bo'ladi.

    Notch signalizatsiyasi tanlangan hujayralar tomonidan Notch ligand ifodasini vaqtinchalik va fazoviy qattiq nazorat bilan tartibga solinadi. Masalan, Dll4 ligandlarining yuqori darajasi timus epiteliya hujayralarida ifodalanadi, bu T hujayrali rivojlanishida Notch signalizatsiyasi uchun anatomik joy yaratadi [12-14]. Teshik signallari, shuningdek, retseptorning epidermal o'sish omili (EGF) domenlarida serin yoki treonin qoldiqlarining O-glikozilatsiyasi bilan tartibga solinadi. Notch signalizatsiyasining O-glikozillanish fenokopiyalarining yo'qolishi [15]. O-glikozilatsiyani N-asetilglukozaminni glycosyltransferase Fringe qo'shishi bilan cho'zish mumkin, bu esa Notch retseptorlarini Delta-ga o'xshab signalli ligandlardan ustun qo'yadi [16]. Genetik o'chirish Fringe Genlar odatda Notch funktsiyasi yo'qolishining fenotiplarini keltirib chiqaradi, shu jumladan T hujayralarining rivojlanishiga ta'sir qiladi [17].

    Dastlabki proteolitik faollashuvdan so'ng Notch signalizatsiyasi FBW7 E3 ubikuitin ligazasi orqali C-terminalli PEST domeni orqali proteazomal degradatsiyaga faol ICNni tez nishonga olish bilan tartibga solinadi. FBW7 mutatsiyalar va kesmalar NOTCH1 PEST domeni Notch tomonidan boshqariladigan T hujayrali o'tkir limfoblastik leykemiyada (T-ALL) aniqlangan. Barcha T-ALL bemor namunalari va hujayra liniyalarining 50% dan ortig'i faollashtiruvchi xususiyatga ega NOTCH1 mutatsiyalar, shu jumladan PEST kesilishi va retseptorlarning faollashishiga olib keladigan membrana-proksimal mutatsiyalar [2,18,19].

    T-hujayrali rivojlanish uchun notch signallari muhim ahamiyatga ega va uning ta'siri T-ALLni haydash uchun buzilishi mumkin [2]. Bizning sharhimizning markazida bo'lmagan kontekstda, onkogen Notch faollashuvining asosiy mutatsion mexanizmlari NOTCH1 hujayradan tashqari heterodimerizatsiya sohasiga ta'sir qiluvchi nuqta mutatsiyalarini o'z ichiga oladi, shu bilan konstitutsiyaviy proteolitik retseptorlarning faollashuviga va hujayra ichidagi NOTCH1 PEST domenini kesib tashlaydigan mutatsiyalarga olib keladi. faollashtirilgandan so'ng uning yarim umrini oshiradi. Bu ikkita mutatsiya klassi bir vaqtning o'zida paydo bo'lishi mumkin NOTCH1 allel, hamkorlikni taklif qiladi. Hammasi faollashtiriladi NOTCH1 mutatsiyalari va ular bilan bog'liq genetik hodisalar kamida 60-70% birlamchi T-ALL holatlarida qayd etilgan, bu kasallikdagi Notch signalizatsiyasining dominant funktsiyasiga mos keladi.

    Xuddi shunday, NOTCH1 va NOTCH2 mutatsiyalar turli B hujayrali limfomalarda uchraydi NOTCH1 surunkali limfotsitik leykemiyada (CLL) takroriy mutatsiyaga uchragan NOTCH2 marginal zonadagi limfoma [20-25]. Bu mutatsiyalar, odatda, ICN degradatsiyaga qarshi himoyasiz bo'lish uchun C-terminalli PEST domenini kesib, ICN aylanishini kamaytiruvchi kadrli yoki bema'nilik mutatsiyalardir. Qizig'i shundaki, hatto aniqlikdan ham mustaqil NOTCH1 mutatsiyalar, CLL holatlarining taxminan 50% bir seriyada BUYUQ baland gen ekspresyon imzosi va boshqa seriyalar 80% hollarda immunohistokimyoviy bo'yash orqali faollashtirilgan NOTCH1 ning ko'payishini aniqladi, bu Notch ligandlari mutatsiyaga uchramagan Notch retseptorlari bilan ham CLLda signalizatsiya qilishini ko'rsatadi [26,27].

    3. T hujayralarining rivojlanishi

    T-hujayra rivojlanishi limfotsitlar progenitatorlari suyak iligi gematopoetik ildiz hujayralaridan ajralib, timusga ko'chib o'tgandan so'ng davom etadi [28]. Ixtisoslashgan timus epiteliya hujayralari uyushgan bosqichma-bosqich yondashuv bo'yicha T hujayralarini rivojlanishiga turtki beradi. Jarayon CD4 va CD8 ning hujayrali yuzasi ifodasi uchun ikki marta salbiy bo'lgan erta timotsitlar bilan boshlanadi. Ushbu jarayonning kümülatif ta'siri peptid-MHC antigen komplekslarini taniy oladigan turli xil repertuarga ega CD4 + va CD8 + T hujayralarining paydo bo'lishidir.

    Notch an'anaviy ravishda T hujayralarining erta rivojlanishidagi roli uchun tasvirlangan. Bu mavzu boshqa joylarda ko'rib chiqilgan [29], lekin biz etuk T hujayralaridagi tushunchalarni talqin qilish bilan bog'liq muhim kuzatuvlarni ajratib ko'rsatamiz. Notch signalizatsiyasi timusdagi T nasl-nasabi majburiyatida muhim rol o'ynaydi, bu rol birinchi marta B limfopoez hisobiga o'ylangan. Genetik inaktivatsiya Teshik 1 yoki uning quyi oqimidagi transkripsiya mashinasi natijasida B guruhining intratimik rivojlanishi uchun ruxsat berilgan gipoplastik timus paydo bo'ladi [3,30]. O'zaro, konstitutsiyaviy faol Notchning haddan tashqari ko'payishi timusdan mustaqil T hujayralarining rivojlanishiga va suyak iligi B hujayralarining rivojlanishini bostirishga olib keladi. Shu bilan birga, Notch timusda miyeloid taqdirini salbiy tartibga soladi [31,32]. Shunday qilib, T/B ikkilik hujayra taqdiri qarorini boshqaruvchi Notchning asl modeli bir nechta muqobil hujayra taqdirini bostirishda Notchning T nasl rivojlanishining yanada murakkab naqshini keltirib chiqardi. Qizig'i shundaki, yaqinda o'tkazilgan ishda suyak iligida limfoid va T chizig'ining spetsifikatsiyasining dastlabki etimik bosqichlarida Notch signalizatsiyasi muhim rol o'ynagan, bu suyak iligi mikro muhitidagi endotelial va endotelial bo'lmagan mezenxim elementlari Dll4 Notch ligand orqali limfoid ajdodlariga signallar berishi mumkinligini ko'rsatdi. [33,34]. Shunga qaramay, suyak iligida Dll4 ifodasining ko'pligi va/yoki uning aniq mikroanatomik taqsimlanishi qat'iy nazorat ostida qolishi kerak, chunki LRF etishmaydigan sichqonlarda Dll4 ning keng tarqalishi boshqa nasllar hisobiga T-hujayradan tashqari ekstrasimik rivojlanishiga olib kelishi mumkin. ,36].

    Limfa tugunlari timusga kirganda, ular timopoez uchun zarur bo'lgan kortikal timik epiteliyda notch ligandlarining zich ifodasini uchratadilar [3,13,14,37,38]. Notch signallari T-hujayradan oldingi retseptorlarni nazorat qilish nuqtasiga qadar saqlanib qoladi, shundan so'ng Notch signalining intensivligi pasayadi [39-42]. Ikkita musbat timotsitlar fiziologik sharoitda notch signalini qabul qilmaydi. Notch ijobiy va salbiy tanlash [43-44] va etuk T hujayralarini periferiyaga chiqarish uchun zarurdir.

    4. Notch signalizatsiyasi etuk T hujayra funktsiyasiga ta'sir qiladi

    Yetuk T hujayralarida Notch signalizatsiyasining muhim roli hozirda mezbonlarni himoya qilish, otoimmunitet va alloimmunitet modellarida aniqlangan (1 -jadval). Notchning etuk T hujayralariga qanday ta'sir qilishini tavsiflovchi ish haddan tashqari ekspressiya tajribalari bilan boshlangan va keyinchalik xulosalar asosida qayta ko'rib chiqilgan. in vivo, funktsiyani yo'qotish strategiyalari.

    Jadval 1. T hujayralarining etuk funktsiyasida Notch signalizatsiyasining rolini tasdiqlovchi eksperimental dalillar.

    Etuk T hujayralarida Notch rolining dastlabki dalillari tolerogen ta'sir ko'rsatadi. Jagged1 ning haddan tashqari ekspensiyasi, chang oqadilar antijeni ifoda etadigan professional antijenlarni taqdim etuvchi hujayralarga (APC) bardoshlik bag'ishladi va CD4 + T hujayralarining differentsiatsiyasini immunosupressiv tartibga soluvchi T hujayralariga (Treg) [72] olib keldi. Shunga o'xshash bardoshlik va Tregning farqlanishi, Jagged1-haddan tashqari oshkor qilingan APClar, Epstein-Barr virusi antijenlarini madaniyatdagi autolog yoki allogenik T hujayralariga taqdim etganida kuzatilgan, bu esa Notchning virus va alloantigenlarga nisbatan bag'rikenglikdagi rolini ko'rsatadi [73,74]. Biroq, bu ortiqcha ifodalash modellari boshqalari bilan yaxshi bog'liq emas edi in vitro APClardagi Notch ligandlari patogen bilan uchrashishga javoban ko'tarilganligi haqidagi topilmalar yallig'lanishga qarshi funktsiyalarni ko'rsatadi [75-77].

    Yaqinda genetik va farmakologik in vivo Funktsiyaning yo'qolishi strategiyasi etuk T hujayralarida Notch signalizatsiyasining dominant proinflamatuar ta'sirini ko'rsatdi. Notch signalizatsiyasi xostlar himoyasida T hujayralarining mustahkam javob berishi uchun muhim ko'rinadi (1 -jadval). Masalan, shartli o'chirish Notch1 va Teshik 2 (lekin alohida emas) sichqonchaning CD4 + T hujayralarida sezgirlikni ta'minladi Leyshmaniya infektsiya [47], bu Notch parazitar infektsiyani nazorat qilish uchun IFNy-sekret qiluvchi hujayralarni yaratish uchun zarur ekanligini ko'rsatadi. Qizig'i shundaki, Dll1 gen visseral leyshmaniozga sezuvchanlik bilan bog'liq [78]. Boshqa infektsiya modellarida Notch2 CD8 + T hujayralari funktsiyasining buzilishi va parazitga sezuvchanlik Trypanosoma kruzi [45]. Genetik Teshik 1 va Notch2 inaktivatsiya CD8 + T hujayralarining ikkalasiga ham javobini buzadi Listeria va gripp infektsiyasi, natijada patogen klirensi buziladi [48,50]. In vivo Dll1 ga qarshi neytrallashtiruvchi antikorning kiritilishi gripp infektsiyasining klirensini ham buzdi va o'limning yuqori bo'lishiga va IFNy ishlab chiqarilishining pasayishiga olib keldi, bu topilma quyidagi hollarda takrorlangan. in vivo g-sekretaza inhibitörleri (GSI) orqali pan-Notch inhibisyonu [49]. Notch signalizatsiyasini blokirovka qilish uchun CD4 + T hujayralarida MAML (DNMAML) ning dominant-manfiy shaklini ifodalash qo'ziqorin yuklarining ko'payishiga olib keldi. Cryptococcus neoformans [51]. Xuddi shunday, Dll4 ga qarshi neytrallashtiruvchi antikor mikobakteriyalar keltirib chiqaradigan o'pka granulomatozining immunitetini zaiflashtiradi, bu sichqonlarda boshqa darajadagi himoya sitokinlar bilan ta'minlanadi [46]. CD4 + T-hujayra reaktsiyasining buzilishi shartli ravishda o'chirilgandan keyin model antijenlari bilan ham kuzatildi. Chap 1/2 yoki Rbpj (o'chirishga qarshi Dll4 APClarda) [70,71]. Umuman olganda, funktsiyaning yo'qolishi yondashuvlari Notch signalizatsiyasining uy egasi himoyasida etuk T hujayralariga proinflamatuar ta'sirini aniqladi, lekin kontekstga xos oqibatlarga olib keldi.

    In vivo otoimmunitet modellarida funktsiyani yo'qotish tajribalari, shuningdek, etuk T hujayralarida Notch signalining dominant proinflamatuar rolini aniqladi (1-jadval). Ko'p sklerozning sichqoncha modelida g-sekretaz inhibitörleri (GSI) tomonidan Notch inhibisyonu kasallikning rivojlanishini sekinlashtirdi [52]. Bu hayajonli topilma, Dll4 va Notch3 uchun tizimli blokirovka qiluvchi antikorlar orqali rollarni taklif qilgan keyingi tadqiqotlar bilan tasdiqlandi [52-56]. Shuningdek, biz DNMAML [57] ifodasi orqali Notch signalidan mahrum bo'lgan T hujayralari bo'lgan sichqonlarda kasalliklardan dramatik himoyani kuzatdik. Bu himoya T hujayralari faollashuvi va ikkilamchi limfoid organlarda differentsiatsiyasiga bog'liq bo'lmagan holda paydo bo'ldi, garchi markaziy asab tizimidagi Notchdan mahrum, miyelin-reaktiv T hujayralari yallig'lanishli IL-17A va IFNy hosil qilmasa ham, maqsadda Notch yo'lining mahalliy ta'sirini ko'rsatadi. organ. Klinik korrelyatsiyalar va boshqa assotsiativ tadqiqotlar, shuningdek, revmatoid artrit va tizimli sklerozni o'z ichiga olgan boshqa otoimmun kasalliklarda Notch rolini taklif qiladi va GSI bilan davolash sichqon modellarida kasalliklarni yaxshilashga imkon beradi [79-81]. Biroq, bu otoimmün kasallik modellari, bu nuqtai nazardan Notch signalizatsiyasining rolini aniqlash uchun ko'proq maqsadli funktsiyalarni yo'qotish strategiyalaridan foydalangan holda keyingi ishlarni talab qiladi.

    T-hujayralardagi notch signallari allogenik suyak iligi transplantatsiyasidan so'ng, qattiq organ transplantatsiyasini rad etish paytida ham, transplantatsiyaga qarshi kasallik (GVHD) paytida ham alloimmunitetning muhim regulyatori bo'lib, biz uni boshqa joyda ko'rib chiqdik [82]. Xostlarni himoya qilish modellarida bo'lgani kabi, dastlabki tadqiqotlar Notch ligandlarining haddan tashqari ta'siriga asoslangan bo'lib, bu T hujayralarida Notch signalizatsiyasining tolerogen ta'sirini ko'rsatdi. Ham Dll1, ham MHC yuklangan alloantigenlarni haddan tashqari ifodalovchi fibroblastlar CD8 + vositachiligida transplantatsiya rad etilishini kechiktirish uchun yurak allogreftlari bo'lgan sichqonlarga qabul qilinishi mumkin edi [83]. Bundan tashqari, Jagged1-ortiqcha ifodalangan APClar (CD40 blokadasi bilan bir qatorda) yurak allograftini rad etishni kechiktirdi [84]. Biroq, infektsiya modellarida va otoimmunitetda kuzatilganidek, in vivo Funktsiyani yo'qotish yondashuvlari o'rniga alloimmunitetda Notch signalining dominant proinflamatuar rolini aniqladi (1-jadval). Kostimulyatsiya blokadasi bilan bir qatorda Dll1-blokirovka qiluvchi antikorlardan foydalanish rad etishni kechiktirdi va MHC bilan mos kelmaydigan yurak transplantatsiyasi sichqonchasi modelida yallig'lanishli sitokin sekretsiyasini kamaytiradi [67]. Xuddi shunday, Dll1 va Dll4 blokirovka qiluvchi antikorlar bilan to'liqroq Notch blokadasi yoki DNMAML yordamida Notch signalizatsiyasining T hujayralariga xos ablasyonu, kostimulyatsiya blokadasisiz yurak allograftini rad etishni kechiktirdi [68]. Qizig'i shundaki, peritransplantatsiya davrida qisqa muddatli Dll1 / 4 blokadasi ushbu modelda CD4 + T-hujayra vositachiligida rad etishga qarshi proektsiyani ta'minlash uchun etarli edi. Shunga o'xshab, yaqinda olib borilgan ishlar MHC bilan mos kelmaydigan yurak va o'pka transplantatsiyasi modellarida transplantatsiyani rad etishni kechiktirishda peri-transplant Notch1 antikor blokadasining rolini ko'rsatdi, shuningdek, inson terisi kimerik inson gematopoetik tizimiga ega sichqonchaga payvand qilingan modelga qo'shimcha ravishda [69] . Bu ish shuni ko'rsatdiki, Tregning anti-CD25 antikorlari orqali kamayishi Notch blokadasining foydali ta'sirini bekor qildi va shartli Teshik 1 Treglarda o'chirish xuddi shunday tarzda transplantatsiyani rad etishni kechiktirishi mumkin.

    GVHD suyak iligi transplantatsiyasidan keyingi alloimmun javobning hayot uchun xavfli oqibati bo'lib, donor T hujayralari retsipient to'qimalariga hujum qiladi [82]. Notch signalizatsiyasi shartli DNMAML ifodasi yoki RBP-Jk [58,59] yo'qolishi orqali donor T hujayralarida bloklanganida, biz MHC bilan mos kelmaydigan transplantlarda GVHD dan dramatik himoya topdik. Biz bu ta'sirlarni shartli ravishda fenokopiya qildik Notch1 va Notch2 donor T hujayralarida delektsiya [60,61]. Shuningdek, biz Dll1 va Dll4 ligandlariga qarshi blokirovka qiluvchi antikorlar yordamida shunga o'xshash himoyani oldik. Notch1 va Dll4 uchun dominant rol kuzatildi. Qizig'i shundaki, transplantatsiya paytida Dll1/4 vaqtinchalik blokadasi GVHDdan uzoq muddatli himoyani ta'minladi. Boshqa guruhlar o'zlarining modellarida etuk T hujayralarida Notch signalizatsiyasini bekor qilgandan so'ng GVHD dan himoyani aniqladilar [62-64]. Bir model Tregsda RBP-Jκ ning shartli yo'qolishidan foydalangan bo'lsa-da, Tregsda Notch signalizatsiyasi GVHD himoyasining asosiy drayveri [64], Tconvs bilan bir qatorda Tregsda Notch signalizatsiyasining yonma-yon shartli o'chirilishi Tconvsda Notch inhibisyonu ekanligini ko'rsatdi. GVHD dan himoya qilish uchun zarur bo'lib qoldi [65].

    Umuman olganda, infektsiya, autoimmunitet va alloimmunitet modellari bo'yicha, in vivo funktsiyani yo'qotish tajribalari etuk T hujayralarida Notch signalizatsiyasining pleomorfik proinflamatuar funktsiyasini aniqladi. Birgalikda bu ish kuchini ko'rsatadi in vivo Notch signalining fiziologik rolini oshkor qilish uchun funktsiyalar yo'qolishi modellari, haddan tashqari eksperiment sifatida, eksperimentlar, bu sozlamalarda, Notch uchun boshqacha zid tolerogen rolni taklif qilgan.

    5. Yetilgan T -hujayralardagi uyali signalli yo'llar

    Etuk sodda CD4 + va CD8 + T hujayralari Notch1 va Notch2 retseptorlarini ifodalaydi [77,85-87], T hujayra retseptorlari (TCR) stimulyatsiyasidan keyin yuqori tartibga solinadigan ifoda bilan [88]. CD4 + T hujayralarining antijenik stimulyatsiyasidan so'ng yorilib ketgan Notch1 ning ortishi ham kuzatildi [85]. Notch1 va Notch2dan tashqari, Notch3 timotsitlar [89] va T-ALL [90] ning rivojlanishiga ta'sirini o'rgangan va hech bo'lmaganda bitta guruh uni yetilgan T hujayralarida [88] aniqlagan. Biroq, tizimli Notch3 blokirovka qiluvchi antikorlar ko'p sklerozning sichqoncha modelida himoyalangan bo'lsa-da [55], uning etuk T hujayralarida rolini ko'rsatadigan genetik funktsiyani yo'qotish ma'lumotlari hozirgacha xabar qilinmagan. Bundan farqli o'laroq, majburiy Notch3 haddan tashqari ifodalash tajribalari yanada o'rganilishi kerak bo'lgan potentsial rolni taklif qildi [91,92].

    Rivojlanayotgan timotsitlarda bo'lgani kabi, etuk T hujayralarida Notch retseptorning proteolitik bo'linishi orqali yadroga o'tadigan va maqsadli genlarning transkripsiya faollashuvini boshlaydigan ICNni chiqarish uchun signal beradi. Notch transkripsiya maqsadlarining tabiati va tartibga solinishi etuk T hujayralarida yaxshi tushunilmagan bo'lib qolmoqda (2 -rasm). Funktsiyalar bo'yicha tajribalar ortdi Hes1 va Dtx1 Notch ligand ta'sirida ifoda [73,93] va biz uning o'zgarishini kuzatdik Dtx1, Hes1, Il2ra va 2 -qism yordamida gen ifodasi in vivo Notch ligand blokadasi bilan alloimmunitet modeli - ilgari boshqa kontekstlarda Notch maqsadlari sifatida aniqlangan barcha genlar [66]. Boshqalar ICN ni bog'lash qobiliyatini topdilar Gzmb targ'ibotchi [45]. Yaqinda ommaviy RNK sekansirovkasidan foydalanib, biz allogeneik suyak iligi transplantatsiyasi paytida Notch inhibisyoni Mik-regulyatsiyalangan genlar guruhining transkripsiyasini buzganligini va T-hujayrali leykemiya va timopoezda aniqlangan maqsadlarga bog'liq bo'lmagan transkripsiya dasturini o'zgartirganini aniqladik [65].

    Shakl 2. Etuk T hujayralarida mumkin bo'lgan Notch transkripsiya maqsadli genlar sinflari. Notch, RBP-Jκ va MAML oilasi a'zosiga qo'shimcha koaktivatorlarni jalb qilish va global miqyosda xromatin tuzilishini kuchaytiruvchi va targ'ibotchilar klasterlarida bog'lash orqali transkripsiyani dinamik ravishda tartibga soladi. Notch transkripsiya maqsadlari bo'yicha genom bo'yicha ko'plab tadqiqotlar timositlar va Notch tomonidan boshqariladigan T hujayrali leykemiya rivojlanishida o'tkazildi, bu etuk T hujayralari uchun noaniq ahamiyatga ega. Shu nuqtai nazardan, Notch T hujayralarining differentsiatsiyasi va funktsiyasi bilan bog'liq tanlangan immunologik muhim genlarning transkripsiyasini o'zgartirishi ko'rsatilgan. Bundan tashqari, klassik tasvirlangan Notch maqsadlarining oz qismi etuk T hujayralariga immunologik ta'sir ko'rsatadi (masalan. Hes1, Dtx1, 2 -qism). Biroq, etiologik T hujayralarida immunologik jihatdan muhim bo'lgan Notch transkripsiya maqsadlari aniqlanishi kerak.

    Notch quyida muhokama qilinganidek, T hujayralarining turli xil tabaqalanishi taqdirini boshqarish uchun zarur bo'lgan bir qator genlarni tartibga solishi ko'rsatilgan. Haqiqatan ham, Notch maqsadli ekanligi ko'rsatilgan Tbx21, Il4, Gata3-1a, Il17a va Rorc (2 -rasm) [52,77,94,95]. Bundan tashqari, Notch to'g'ridan -to'g'ri tartibga solinishi ko'rsatilgan Ifng ga bog'lash orqali Ifng CNS-11 kuchaytirgichi [96]. Biroq, Notch signalizatsiyasining transkripsiya maqsadlari timotsitlar va malign hujayralarni rivojlanishida ancha yaxshi o'rganilgan bo'lib qolmoqda. Bu topilmalarni etuk T hujayralariga qanchalik qo'llash mumkinligi noma'lum, chunki ko'plab maqsadlar hujayra turiga va kontekstga bog'liq ekanligi aniqlandi. Masalan, IL7RA Timotsitlar va T-ALLda yaxshi tasdiqlangan Notch maqsadli geni bo'lgan, ammo uni etuk T hujayralarida o'rganish kerak [10,97-99]. Qanday bo'lmasin, T-hujayrali leykemiyada ko'rsatilgandek, ICN/RBP-Jκ bog'lanish joylarining faqat kichik bir qismi dinamik ravishda tartibga solinadi.

    Rivojlanayotgan ma'lumotlar, shuningdek, kanonik bo'lmagan Notch signalizatsiyasi uchun potentsial rolni ko'rsatadi, bunda Notch RBP-Jk, MAML va boshqa koaktivatorlar [52,93,100-102] bilan transkripsiyani boshqarish uchun yadroga ICN translokatsiyasidan mustaqil ravishda biologik funktsiyalarni bajaradi. Meva chivinlari va madaniyatli sutemizuvchilar hujayralari birinchi marta Notch signallariga transkripsiya faollashuv kompleksidan qat'i nazar javob berishlari haqida xabar berilgan [103,104]. Etuk T hujayralarida kanonik bo'lmagan Notch signalizatsiya yo'llarining rollari ham taklif qilingan [52,93,101,102]. Bu yo'llarga Tbx21 regulyatsiyasi va NF-kB aktivatsiyasi orqali signal berish kiradi. Haqiqatan ham, ICN qurilmada murakkab deb topildi Tbx21 targ'ibotchi va NF-κB yo'l oralig'i bilan to'g'ridan-to'g'ri o'zaro ta'sir qiladi, bu etuk T hujayralarida kanonik bo'lmagan Notch signalizatsiyasi rolini qo'llab-quvvatlaydi.

    Umuman olganda, notonik signal signalini aniqlashning eng qat'iy strategiyasi-bu Notch retseptorlarining genetik yoki farmakologik bekor qilinishi bilan uning transkripsiya mexanizmining yo'q qilinishi yoki buzilishi o'rtasidagi fenotipik kelishmovchilikni ko'rsatish (RBP-Jκ yoki DNMAML ifodasini yo'qotish orqali). Masalan, CD4 + T hujayralari tomonidan IFNy ishlab chiqarishni nazorat qilishda kanonik bo'lmagan Notch signalizatsiyasining roli taklif qilingan. Leyshmaniya infektsiya [47]. Notch1 va Teshik 2 T hujayralarida inaktivatsiya infektsiyaga moyillikni ta'minladi, ammo shunga o'xshash shartli RBP-Jk yo'qolgan sichqonlar himoyalangan bo'lib qoldi. Ushbu ma'lumotlar ushbu sharoitda Notch signalizatsiyasining kanonik bo'lmagan yo'lini tasdiqlaydi, ammo aniq molekulyar mexanizmlar aniqlanishi kerak. Xuddi shunday qat'iy genetik yondashuv Treglarda kanonik bo'lmagan Notch signalizatsiyasi uchun cheklangan rolni topdi, ammo kanonik signalizatsiya dominant yo'l bo'lib qoldi [64]. Notch1 va RBP-Jκ etishmaydigan Treglarning kengayishi va bag'rikenglik induksiyasi kuchayganligini aniqlagandan so'ng, mualliflar Treglarda ICN ifodasini Treg disfunktsiyasi va otoimmunitetni qo'zg'atishga majbur qilishdi. ICN-ekspressiv hujayralarda RBP-Jκ ning yo'qolishi bu fenotiplarning ko'pini qutqarib qoldi (kanonik yo'lni afzal ko'radi). Biroq, tanlangan topilmalar, masalan, demetilatsiyaning buzilishi kabi ta'sir ko'rsatmadi Foxp3, kanonik bo'lmagan Notch signalizatsiyasi uchun rolni taklif qiladi. Umuman olganda, kanonik bo'lmagan signalizatsiya ba'zi hollarda etuk T hujayralarida ro'y beradi in vivo, funktsiyaning yo'qolishi bo'yicha tadqiqotlar ko'pchilik kontekstlarda ushbu hodisaning dolzarbligini aniqlash uchun muhim bo'lib qolmoqda.

    6. T-hujayralarni differensiallashda tishli signalizatsiya

    Funktsiya yo'qolishidan foydalanish, in vivo Modellashtirish, shuningdek, Notchning etuk T hujayralarining differentsiatsiyasida qanday ishlashiga aniqlik kiritdi. Differentsiatsiya - bu ma'lum bir tahdid turiga qarshi kurashda eng samarali bo'lgan ma'lum funktsiyalar majmuasiga qarshi immunitetning qutblanishi. Differentsiya paytida, bu CD4 + T hujayralari APClarga juxtacrine hujayra -hujayra signallari va eriydigan sitokinlar orqali javob beradi. Differensiatsiyaning eng ko'zga ko'ringan holatlaridan ikkitasi T-yardımchi 1 (Th1) hujayra taqdirini o'z ichiga oladi, bu erda CD4 + T hujayralari T-bet transkripsiya faktori (kodlangan) tomonidan boshqariladi. Tbx21), IFNγni viruslar va hujayra ichidagi patogenlar [105] va Th2 hujayralari taqdiri bilan kurashish uchun qiling, bu erda T hujayralari GATA3 transkripsiyasi faktori orqali IL-4, IL-5 va IL-13 ishlab chiqarish orqali gelmint parazitlari bilan kurashadi [106-108]. Garchi boshqalar T hujayrasini differentsiatsiyalashda Notch rolini ko'rib chiqishgan bo'lsa -da, biz qarama -qarshi dalillarni tortish va kattaroq yangi mavzularni ochish uchun adabiyotni tanqidiy baholashga e'tibor qaratamiz [109].

    Notchning etuk T hujayralari differentsiatsiyasiga qanday ta'sir qilishi mumkinligi haqidagi dastlabki model shuni ko'rsatadiki, Notch bipotentsial kalit bo'lib, Th1 va Th2 hujayra taqdirlari o'rtasida almashinadi va natijasi Notch ligandlarining tabiatiga bog'liq bo'ladi. Darhaqiqat, dastlabki ishlar shuni ko'rsatdiki, APLlarda Dll4 va Jagged1 notch ligandlarining haddan tashqari haddan tashqari oshishi CD4 + T hujayralarining ligandga xos farqlanishiga olib keladi, natijada Th1 yoki Th2 hujayra taqdiriga to'g'ri keladi [77].

    Biroq, yaqinda taklif qilingan model Notch T-hujayralarining farqlanishining xolis kuchaytirgichi rolini o'ynaydi, mavjud ma'lumotlarga eng mos kelishi mumkin [96]. Kuchaytirgich modeli qarama-qarshi transkripsiyaviy differentsiatsiya dasturlari, shu jumladan maqsadni aniqlashda rol o'ynaydigan Notch gen ekspressiyasini boshqaradigan qarama-qarshi topilmalarni sintez qilishga yordam beradi. Tbx21, Il4, Gata3-1a, Il17a va Rorc [52,77,94,95]. An amplifier model clarifies seemingly contradictory data that suggested roles for Notch signalling in promoting either Th1 or Th2 responses under different polarizing conditions. For example, Notch was reported to promote Th1 differentiation as Dll1 could drive Th1 commitment ex vivo [92], while Notch blockade via GSI suppressed Th1 differentiation in vivo [52]. Others proposed that Notch promoted Th2 differentiation, as DNMAML expression led to impaired IL-4 and Th2 cytokine production and impaired defence against Trichuris muris [94,110]. An amplifier model, whereby Notch helps sustain expression of different gene targets for both Th1 and Th2, synthesizes these data and makes sense of how a fundamental cell signalling pathway can drive differentiation of several distinct lineages. In other words, Notch regulates distinct transcriptional programmes for differentiation to various T cell fates by sensitizing T cells to cytokine-derived and other regulatory signals. This model was proposed after experiments using conditional expression of DNMAML to ablate Notch signalling found that Notch had no impact on Th2 initiation following infection with the helminth T. muris, but did affect maintenance of Th1 and Th2 programmes [96]. Notch was also shown to be needed for the maintenance of the Th17 response (another differentiation state characterized by IL-17 expression that is important in immunity against extracellular pathogens and associated with autoimmune conditions). The amplifier model is further supported by mechanistic work showing that Dll4 expression on APCs could activate CD4 + T cells via augmenting PI3 K pathway signalling downstream of CD28 co-stimulation through a pattern of activity reminiscent of costimulatory signals [70].

    Beyond Th1, Th2 and Th17, Notch has also been linked to other differentiation states. Th9 responses, so called for the production of the cytokine IL-9, are related to Th2 in anti-helminth immunity and appear to be implicated in certain autoimmune diseases. It also requires Notch signals as loss of Notch1/2 receptors abrogated the development of Th9 cells, while ICN, RBP-Jκ and Smad3 (downstream of TGFβ) were all found to cooperatively bind the Il9 promoter [53].

    Notch also regulates T cell differentiation into follicular T helper cells (Tfh). Tfh cells specialize in helping B cells during isotype class switching and affinity maturation via CD40 L and secreted cytokines [111]. Notch1/2 deletion in T cells resulted in decreased numbers of Tfh and IL-21 production in response to parasitic infection and hapten immunization [112], translating into impaired germinal centre formation and IgG1 production independently of Notch's effects on IL-4.

    Notch signalling may also regulate Treg differentiation, which mediates peripheral tolerance via FoxP3-dependent mechanisms [113]. Overexpression studies first suggested that Jagged ligands were capable of promoting Treg expansion [73]. Indeed, cultured T cells exposed to TGFβ, which assume a Treg-like phenotype, lost this ability upon addition of GSI [114]. Biroq, in vivo loss-of-function approaches suggested an alternative role for Notch in Tregs. Genetic Notch1 yoki Rbpj inactivation instead led to a ‘super-regulatory’ phenotype [64]. Consistent with this work, blocking Notch signalling in vivo through genetic or pharmacologic means during allogeneic bone marrow transplantation resulted in Treg expansion [58,66]. Umuman olganda, in vivo work suggests that Notch signalling curtails Treg function.

    7. Source and specificity of Notch ligands

    In vivo T cell conditional abrogation of Notch receptors and of the Notch transcriptional machinery (either via RBP-Jκ loss or DNMAML expression) has been the most robust approach to glean insights into the pleotropic effects of Notch in mature T cells. Ligand-targeted genetic strategies have proven initially more challenging, given limited insight into cellular sources of ligands and possibly different or redundant effects from different ligands. Loss-of-function strategies targeting ligands therefore mostly relied on systemic blocking antibodies. Otherwise, many experiments have depended upon ligand over-expression models, which are hypothesis-generating but less physiologically relevant.

    In development, the thymic epithelial cell niche where Notch ligands are provided to early thymocytes has been well characterized (figure 3) [12–14]. The corollary niche for mature T cells in the periphery is only beginning to emerge. Initial focus centred on professional APCs as the suspected cellular source of Notch ligands, as they provide antigen and multiple costimulatory signals during T cell activation. Indeed, Notch ligands are expressed by APCs and in vitro experiments where Notch ligands were induced by Toll-like receptor (TLR) agonism suggested that APCs could be the cellular source of ligands [77,115,116]. Furthermore, Notch ligands upregulated in a subpopulation of APCs from mice receiving allogeneic bone marrow transplantation could activate T cells in vitro in a ligand-dependent fashion [63].

    Figure 3. The Notch niche in primary and secondary lymphoid organs. (a) Developing CD4 − CD8 − (‘double-negative’) thymocytes receive essential Notch signals from Delta-like 4 Notch ligands expressed by thymic epithelial cells. These ligands interact with Notch1 receptors in developing T cells. The specialized thymic niche for T cell development also releases chemokines to attract early T lineage progenitors and Stem Cell Factor (SCF) to support their survival. (b) Mature T cells receive Notch signals from Delta-like 1 and 4 Notch ligands expressed by non-haematopoietic fibroblastic stromal cells in secondary lymphoid organs. These ligands interact with Notch1 and Notch2 expressed by mature T cells. This niche also provides chemokines to attract circulating T cells in the periphery and an IL-7 pro-survival signal.

    However, the physiologic relevance of in vitro experiments suggesting APCs as the source of Notch ligands for mature T cells had not been rigorously confirmed with in vivo experimentation. On the contrary, loss-of-function in vivo experiments uncovered a non-haematopoietic source of Notch ligands. This was first suggested for marginal zone B (MZB) cells—another lymphocyte population—as bone marrow chimeras identified the source of Dll1 necessary to generate MZBs to be non-haematopoietic [117]. This was followed by an elegant series of experiments whereby Dll1 va Dll4 were conditionally inactivated in non-haematopoietic secondary lymphoid organ (SLO) stromal cell populations that expressed a Ccl19-driven Cre recombinase [118]. By lineage tracing cells expressing the Ccl19-Cre transgene, candidate stromal cell subpopulations were defined among Dll1-expressing cells in the spleen (CD45 − CD31 − PDPN − ) responsible for MZB generation and among Dll4-expressing cells in lymph nodes (CD45 − CD31 − CD35 +/− PDPN + ) necessary for Tfh differentiation. The role for these non-haematopoietic stromal cells in SLOs was particularly intriguing given that the only other known niche for Notch signalling in the thymus similarly depends upon Notch ligand expression by non-haematopoietic cell types (thymic epithelial cells). Past work had also found high levels of Dll1 and Dll4 expression on blood and lymphatic endothelial cell populations [117,119–122]. Endothelial cell populations had been suggested to be the source of Notch ligands in developing liver and neural stem cells [123,124]. Though endothelial cells were also implicated as the ligand source for immune cells [117], more recent work instead points to a non-haematopoietic, non-endothelial cell source [118].

    In alloimmunity and GVHD, we found the cellular source of Notch ligands to be non-haematopoietic as well [66]. This finding was unexpected given prior work suggesting that donor and host APCs are critical to activate alloreactive donor T cells in GVHD [125,126]. Foydalanish Ccl19-Cre-driven Dll1 va Dll4 inactivation, we identified a non-haematopoietic SLO stromal cell subpopulation (CD45 − CD31 − PDPN + CD157 + ) as the likely cellular source of Dll1/Dll4 ligand in GVHD [66]. These fibroblastic stromal cells are believed to reside predominantly in the T zone of the SLO. It is currently unknown why these non-haematopoietic stromal cells are the physiologically relevant source of Notch ligands in allogeneic transplant. It is interesting to speculate that the expression of T-cell chemoattractants CCL19 and CCL21 may render these cells analogous to thymic epithelial cells, which express Dll4 as well as CCL21/25 and CXCL12 under the control of the Foxn1 transcription factor (figure 3) [12]. SLO fibroblastic stromal cells also secrete IL-7, which is necessary for mature T cell survival [127]. Future work should investigate how broadly relevant SLO stromal cells are as a source of Notch ligands in other immunological contexts.

    A number of reports have suggested different functional effects of the four agonistic Notch ligands. Data from conditional genetic deletion are limited given uncertainty about the relevant cellular source of ligands. However, work in stromal cells found Dll1 expression in a splenic stromal cell subpopulation critical for MZB cells, while identifying Dll4 expression in lymph nodes as essential for Tfh differentiation [118]. These data fit with our work that found a dominant role for Dll4 over Dll1 in alloreactivity using both blocking antibodies and selective deletion in Ccl19-expressing stromal cells [60,66]. Other experiments, relying upon in vitro and overexpression models, suggested that different ligands induce distinct patterns of differentiation, with Delta-like family members associated with a Th1 response and Jagged with Th2. However, much of this work could be confounded by TLR agonism, which selectively upregulates Delta-like family members over Jagged, making it unclear how much of the Th1/Th2 differentiation bias was instead due to independent effects of TLR agonism [76,77,128]. Blocking antibodies have also suggested different effects from different ligands. Antibodies blocking Dll1 and Dll4—and not Jagged1—could suppress deleterious effects in a multiple sclerosis mouse model [54,129]. The mechanistic basis for qualitatively different signals from Delta-like and Jagged family members, which both signal similarly through the Notch receptor, is unclear. Indeed, another group using ligand overexpression in APCs did not observe a Delta-like/Jagged bias in Th1/Th2 instruction in the absence of polarizing cytokines [130]. It may be that the seemingly different effects of the different ligands are instead attributable to different cellular sources of ligands. Overall, loss-of-function in vivo approaches promise to provide the most reliable and physiologically relevant answers.

    8. Concluding remarks

    A picture of how Notch contributes to the functions of mature T cells in the periphery is slowly coming into view, although many outstanding questions remain. Importantly, lessons learned from studying the role of Notch in T cell development bore significantly on the study of Notch in mature T cells and will play an important role in future experiments to resolve open questions. Specifically, the value of in vivo, loss-of-function experiments in this context cannot be overstated. This was seen during experiments deciphering downstream Notch signalling in T cells, mapping the role of Notch in T cell differentiation and identifying the cellular source of Notch ligands. Furthermore, the concept of Notch as a bimodal switch responsible for binary cell fate decisions had to be revised, both in developing and in mature T cells, to make way for a more nuanced picture of Notch as an amplifier of other activating signals. Finally, recent work suggested that a wider range of candidate cellular sources of ligands should be considered, as non-haematopoietic SLO stromal cells have been convincingly shown to play a role in at least in some settings, even though the bulk of the literature had focused on haematopoietic APCs.

    To date, it remains unclear how broadly important stromal cells are as cellular sources of Notch ligands and to what extent other cells, including haematopoietic APCs, provide Notch signals to T cells in the periphery. Beyond TLR signalling, it is unknown which signalling pathways or transcriptional machinery control the expression of Notch ligands to impact mature T cell function. Characterization of the niche for Notch ligand presentation, as has been done in the thymus for developing T cells, remains to be done. Additionally, the downstream targets of Notch signalling in mature T cells remain ill-defined and insights into how Notch effects gene expression often rely on extrapolation from work in T cell leukaemia and developing thymocytes. Finally, if different Notch ligands do indeed physiologically provoke different functional consequences in mature T cells, the mechanistic basis for this observation remains poorly understood. The answers to these remaining questions will become particularly relevant in revealing new ways to interfere with the Notch pathway so that it might be targeted therapeutically.


    Notch Signaling

    The Notch pathway regulates cell proliferation, cell fate, differentiation, and cell death in all metazoans. Notch itself is a cell-surface receptor that transduces short-range signals by interacting with transmembrane ligands such as Delta (termed Delta-like in humans) and Serrate (termed Jagged in humans) on neighboring cells (Fig. 1). Some soluble ligands have also been identified in Caenorhabditis elegans, but these bind to Notch together with transmembrane adaptors (Komatsu et al. 2008). Ligand binding leads to cleavage and release of the Notch intracellular domain (NICD), which then travels to the nucleus to regulate transcriptional complexes containing the DNA-binding protein CBF1/RBPjk/Su(H)/Lag1 (CSL).

    Notch signaling (simplified view).

    Following their synthesis, Notch receptors are cleaved by protein convertases during exocytosis at site 1 (S1), which regulates their trafficking and signaling activity (Logeat et al. 1998 Gordon et al. 2009). During passage through the Golgi, they can be glycosylated by glycosyltransferases such as Fringe, which determines the subsequent response to different subfamilies of ligands. These and other posttranslational modifications of the receptors and ligands tune the amplitude and timing of Notch activity to generate context-specific signals. Several proteins, including E3 ubiquitin ligases (e.g., Deltex and Nedd4), Numb, and α-adaptin, regulate the steady-state levels of the Notch receptor at the cell surface. In signal-sending cells, E3 ubiquitin ligases (Neur and MIB) similarly ubiquitylate the intracellular domain of the ligand to promote epsin-mediated endocytosis, which is associated with ligand activation (Fig. 2).

    Following ligand binding, signaling is initiated when endocytosis of ligand–receptor complexes induces unfolding of a juxtamembrane negative control region (NRR) unique to Notch proteins. Unfolding of the NRR allows access by the protease ADAM10 (also known as KUZ), which removes the Notch extracellular domain by cleaving at site 2 (S2) γ-secretase then cleaves Notch within its transmembrane domain at site 3 (S3) to release various forms of the NICD. Those that have valine or methionine residues at the amino terminus escape the N-end-rule degradation pathway (Tagami et al. 2008) and are stable enough to impact transcription (see below). Interestingly, productive interactions between Notch and its ligands occur when these are present on neighboring cells (i.e., in trans) when receptor and ligand are present on the same cell (i.e., interactions are in cis), activation is inhibited. cis interactions thus determine whether a cell will signal (the ligand is more abundant than Notch) or receive (Notch is more abundant than the ligand) (Sprinzak et al. 2010). Alternatively, in some cases ligand and receptors can be segregated into different subdomains to allow simultaneous transmission and reception of signals (Luty et al. 2007).

    Only one nuclear protein is known to mediate the bulk of Notch signals: CSL (Kopan and Ilagan 2009). CSL is a DNA-binding adaptor that interacts with many proteins to build either repressor complexes, which include histone deacetylases (HDACs) that preserve a closed chromatin conformation, or activating complexes, which contain NICD, along with other proteins including histone acetyltransferases (HATs) that open up chromatin. In canonical, CSL-mediated Notch signaling, NICD translocates to the nucleus, binds to CSL, and helps recruit the adaptor protein Mastermind-like (MAML) (Kopan and Ilagan 2009). MAML recruits the HAT p300 and components of the transcription machinery. Thus, every cleaved Notch molecule generates one signaling unit, and tuning the effectiveness of receptor–ligand interaction directly determines the amount of NICD in the nucleus. During the transcriptional activation process, NICD is phosphorylated on a degron within its PEST domain by kinases such as cyclin-dependent kinase 8 (CDK8) and targeted for proteasome-mediated degradation by E3 ubiquitin ligases such as Sel10 (also known as Fbw7). This limits the half-life of a canonical Notch signal and resets the cell for the next pulse of signaling.

    In addition to the canonical signals, mounting evidence indicates that CSL-independent activities of Notch also regulate vertebrate (Rangarajan et al. 2001 Demehri et al. 2008) and invertebrate (Ramain et al. 2001) development, but the biochemical details of this aspect of the pathway are yet to be uncovered. In the absence of ligand, Notch may also be involved in other cellular processes, such as regulating the stability of β-catenin (Sanders et al. 2009), a component of the Wnt signaling pathway (Nusse 2012).

    Under most physiological conditions, unbound Notch receptors simply recycle or are targeted for lysosomal degradation. With one exception (Mukherjee et al. 2011), only pathological or experimental conditions are known to lead to receptor activation without ligand. These include mutations in the NRR domain (Weng et al. 2004), overexpression of Notch with ADAM proteases, and exposure to calcium chelators (Bozkulak and Weinmaster 2009 van Tetering et al. 2009), all of which expose Notch to shedding by ADAM17 (also known as TACE). Notch can also become activated when ESCRT components are mutated (Moberg et al. 2005 Thompson et al. 2005 Vaccari and Bilder 2005), which delays entry into the lysosome and permits ligand-independent activation. The frequent activation of Notch by mutations in T-cell acute lymphoblastic leukemia and its frequent inactivation in head and neck squamous cell carcinomas (Agrawal et al. 2011 Stransky et al. 2011) illustrate the importance of the pathway for control of cell fate and proliferation and the severe consequences of its dysregulation.


    Activation of Notch Signaling Pathway

    The Notch signaling pathway is divided into canonical and non-canonical pathways depending on whether RBP-J&kappa is involved in pathway conduction.

    The canonical Notch signaling pathway process is as follows:

    The unactivated Notch receptor releases a soluble intracellular domain (NICD) after three hydrolysiss. Subsequently, the NICD translocates to the nucleus, where it forms a complex with the DNA binding protein CSL, displacing a histone deacetylase (HDAc)-co-repressor (CoR) complex from CSL. Components of an activation complex, such as MAML1 and histone acetyltransferases (HATs), are recruited to the NICD-CSL complex, leading to the transcriptional activation of Notch target genes.

    Notch signal changes are closely related to the occurrence and development of tumors, genetic diseases, autoimmune diseases and other diseases. The study of this pathway can provide a target for the treatment of diseases.


    Overview of Notch Signaling Pathways

    The Notch family of receptors includes Notch-1, -2, -3, and -4 are highly conserved proteins with a wide range of physiological roles including regulating cell fate, proliferation, angiogenesis, cell survival, and the immune response. Like many other proteins associated with these processes, aberrant Notch activity is reported to have complex and context-dependent effects on tumorigenesis. Upon translation, Notch undergoes several pre-processing steps during its transport to the membrane. These include the addition of O-fucose by O-fucosyltransferase 1 (POFUT1) in the endoplasmic reticulum and, in the Golgi, the addition of N-acetylglucosamine by any of three N-acetylglucosaminetransferases that in vertebrates include Lunatic Fringe (LFNG), Manic Fringe (MFNG), and Radical Fringe (RFNG). Also in the Golgi, Notch is cleaved by Furin to produce a heterodimer consisting of the Notch intracellular domain (NICD) and the Notch extracellular domain (NECD). The heterodimer is then transported to the membrane where it exists as a single pass transmembrane protein. Notch is thought to be in a cycling state that includes endocytosis and re-insertion into the membrane or it may be targeted for lysosomal degradation.

    Notch is activated by a unique process that includes ligand binding and multistep proteolytic processing. Invertebrate, Notch ligands include Delta, Serrate, and Lag2 (DSL), while their DSL counterparts in mammals include Delta-like (DLL)-1, -3, -4, Jagged 1, and Jagged 2. Like Notch, DSL ligands are single pass transmembrane receptors and typical Notch activation includes direct cell-cell interaction (trans-activation). Subsequent to binding Notch, the intracellular domain of the Notch ligand is ubiquitinated via the E3 ligase Mind Bomb-1. This initiates endocytosis of the Notch ligand/NECD complex into the ligand-expressing cell. Common endocytic factors have been implicated in this process including Clathrin, Dynamin, Epsin, and Picalm. The mechanical forces generated by these endocytosis-related events may be important for the next steps in the Notch pathway that include sequential proteolytic cleavage of Notch. Notch is first cleaved by TACE/ADAM17 and then the gamma-Secretase complex that includes Presenilin, PSENEN/PEN-2, APH1, and Nicastrin. Whether gamma-Secretase cleavage occurs at the membrane or the endosomal compartment is still a matter of investigation. After its cleavage, the NICD is released into the cytosol and translocated to the nucleus.

    Notch activity is primarily dependent on its ability to regulate gene transcription. Recombination Signal Binding Protein for Immunoglobulin Kappa J Region (RBPj) plays a crucial role in Notch-mediated gene transcription. RBPj is also known as CBF-1, or CSL based on its mammalian (CBF-1), Drosofila (Suppressor of Hairless), and C. elegans (Lag-2) orthologs. In the absence of Notch activation, CSL/RBPj acts as a transcriptional repressor in complex with a growing list of co-repressors, linker proteins, and enzymes such as histone deacetylases (HDACs). In the nucleus the NICD displaces transcriptional repressors and forms a complex with CSL/RBPj and Mastermind-like (MAML). MAML recruits transcriptional co-activators, such as the histone acetyltransferase p300, forming a Notch activator complex that culminates in the transcription of Notch target genes. The number of proteins associated with regulating the activator complex continues to grow. There are kinases that can directly phosphorylate and positively or negatively regulate the NICD. In addition, a range of DNA-binding factors and proteins that directly interact with the NICD exists that can either promote or inhibit transcription depending on the context. Turnover of the NICD is high and phosphorylation by CDK8 promotes recognition by the E3 ligase FBW7, resulting in NICD ubiquitination and proteasomal degradation. There appears to be a complex equilibrium in place, and the balance between of the opposing regulators that dictate the overall level of Notch activity.

    Binding of Notch by DSL ligands and transcriptional activation involving CSL/RBPj is considered the canonical Notch pathway. However, descriptions of non-canonical signaling continue to be described. Several non-canonical Notch ligands have been identified that have varied effects including the inhibition or activation of the Notch pathways. In addition, it is evident that there is crosstalk between Notch and other signaling pathways, including Akt/mTOR, NF kappa B, Wnt/beta-Catenin, and others.


    Activation of Notch Signaling Pathway

    The Notch signaling pathway is divided into canonical and non-canonical pathways depending on whether RBP-J&kappa is involved in pathway conduction.

    The canonical Notch signaling pathway process is as follows:

    The unactivated Notch receptor releases a soluble intracellular domain (NICD) after three hydrolysiss. Subsequently, the NICD translocates to the nucleus, where it forms a complex with the DNA binding protein CSL, displacing a histone deacetylase (HDAc)-co-repressor (CoR) complex from CSL. Components of an activation complex, such as MAML1 and histone acetyltransferases (HATs), are recruited to the NICD-CSL complex, leading to the transcriptional activation of Notch target genes.

    Notch signal changes are closely related to the occurrence and development of tumors, genetic diseases, autoimmune diseases and other diseases. The study of this pathway can provide a target for the treatment of diseases.


    Cis-activation in the Notch signaling pathway

    The Notch signaling pathway consists of transmembrane ligands and receptors that can interact both within the same cell (cis) and across cell boundaries (trans). Previous work has shown that cis-interactions act to inhibit productive signaling. Here, by analyzing Notch activation in single cells while controlling cell density and ligand expression level, we show that cis-ligands can in fact activate Notch receptors. Bu cis-activation process resembles trans-activation in its ligand level dependence, susceptibility to cis-inhibition, and sensitivity to Fringe modification. Cis-activation occurred for multiple ligand-receptor pairs, in diverse cell types, and affected survival and differentiation in neural stem cells. Finally, mathematical modeling shows how cis-activation could potentially expand the capabilities of Notch signaling, for example enabling “negative” signaling. These results establish cis-activation as a prevalent mode of signaling in the Notch pathway, and should contribute to a more complete understanding of how Notch signaling functions in developmental, physiological, and biomedical contexts.


    Contents

    Notch was discovered in a mutant Drosofila in March 1913 in the lab of Thomas Hunt Morgan. [2] This mutant emerged after several generations of crossing out and back-crossing beaded winged flies with wild type flies and was first characterized by John S. Dexter. [3] The most frequently observed phenotype in Notch mutant flies is the appearance of a concave serration at the most distal end of the wings, for which the gene is named, accompanied by the absence of marginal bristles. [4] [5] This mutant was found to be a sex-linked dominant on the X chromosome that could only be observed in heterozygous females as it was lethal in males and homozygous females. [2] The first Notch allele was established in 1917 by C.W. Metz and C.B. Bridges. [6] In the late 1930s, studies of fly embryogenesis done by Donald F. Poulson provided the first indication of Notch's role in development. [7] Notch-8 mutant males exhibited a lack of the inner germ layers, the endoderm and mesoderm, that resulted in failure to undergo later morphogenesis embryonic lethality. Later studies in early Drosofila neurogenesis provided some of the first indications of Notch's roll in cell-cell signaling, as the nervous system in Notch mutants was developed by sacrificing hypodermal cells. [8]

    Starting in the 1980s researchers began to gain further insights into Notch function through genetic and molecular experiments. Genetic screens conducted in Drosofila led to the identification of several proteins that play a central role in Notch signaling, including Enhancer of split, [8] Master mind, Delta, [9] Suppressor of Hairless (CSL), [10] and Serrate. [11] At the same time, the Notch gene was successfully sequenced [12] [13] and cloned, [14] [15] providing insights into the molecular architecture of Notch proteins and led to identification of Notch homologs in Caenorhabditis elegans (C. elegans) [16] [17] [18] and eventually in mammals.

    In the early 1990s Notch was increasingly implicated as the receptor of a previously unknown intercellular signal pathway [19] [20] in which the NICD is transported to the nucleus where it acts as a transcription factor to directly regulate target genes. [21] [22] [23] The release of the NICD was found to be as a result of proteolytic cleavage of the transmembrane protein through the actions of the γ-secretase complex catalytic subunit Presenilin. This was a significant interaction as Presenilin is implicated in the development of Alzheimer's disease. [24] This and further research into the mechanism of Notch signaling led to research that would further connect Notch to a wide range of human diseases.

    Drosofila contain a single Notch protein, C. elegans contain two redundant notch paralogs, Lin-12 [25] and GLP-1, [18] [26] and humans have four Notch variants, Notch 1-4. Although variations exist between homologs, there are a set of highly conserved structures found in all Notch family proteins. The protein can broadly be split into the Notch extracellular domain (NECD) and Notch intracellular domain (NICD) joined together by a single-pass transmembrane domain (TM).

    The NECD contains 36 EGF repeats in Drosofila, [13] 28-36 in humans, and 13 and 10 in C. elegans Lin-12 and GLP-1 respectively. [27] These repeats are heavily modified through O-glycoslyation [28] and the addition of specific O-linked glycans has been shown to be necessary for proper function. The EGF repeats are followed by three cysteine-rich Lin-12/Notch Repeats (LNR) and a heterodimerization (HD) domain. Together the LNR and HD compose the negative regulatory region adjacent to the cell membrane and help prevent signaling in the absence of ligand binding.

    The NICD acts as a transcription factor that is released after ligand binding triggers its cleavage. It contains a nuclear localization sequence (NLS) that mediates its translocation to the nucleus. where it forms a transcriptional complex along with several other transcription factors. Once in the nucleus, several ankyrin repeats (ANK) and the RAM domain interactions between the NICD and CSL proteins to form a transcriptional activation complex. [29] In humans, an additional PEST domain plays a role in NICD degradation. [30]

    Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells. In Drosophila, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development. This protein functions as a receptor for membrane bound ligands, and may play multiple roles during development. [31] A deficiency can be associated with bicuspid aortic valve. [32]

    There is evidence that activated Notch 1 and Notch 3 promote differentiation of progenitor cells into astroglia. [33] Notch 1, then activated before birth, induces radial glia differentiation, [34] but postnatally induces the differentiation into astrocytes. [35] One study shows that Notch-1 cascade is activated by Reelin in an unidentified way. [36] Reelin and Notch1 cooperate in the development of the dentate gyrus, according to another. [37]

    Notch signaling is triggered via direct cell-to-cell contact, mediated by interactions between the Notch receptor protein in the signal receiving cell and a ligand in an adjacent signal transmitting cell. These type 1 single pass transmembrane proteins fall into the Delta/Serrate/Lag-2 (DSL) family of proteins which is named after the three canonical Notch ligands. [19] Delta and Serrate are found in Drosofila while Lag-2 is found in C. elegans. Humans contain 3 Delta homologs, Delta-like 1, 3, and 4, as well as two Serrate homologs, Jagged 1 and 2. Notch proteins consist of a relatively short intracellular domain and a large extracellular domain with one or more EGF motifs and a N-terminal DSL-binding motif. EGF repeats 11-12 on the Notch extracellular domain have been shown to be necessary and sufficient for trans signaling interactions between Notch and its ligands. [38] Additionally, EGF repeats 24-29 have been implicated in inhibition of cis interactions between Notch and ligands co-expressed in the same cell. [39]

    In order for a signaling event to occur, the Notch protein must be cleaved at several sites. In humans, Notch is first cleaved in the NRR domain by Furin while being processed in the trans-Golgi network before being presented on the cell surface as a heterodimer. [40] [41] Drosofila Notch does not require this cleavage for signaling to occur, [42] and there is some evidence that suggests that LIN-12 and GLP-1 are cleaved at this site in C. elegans.

    Release of the NICD is achieved after an additional two cleavage events to Notch. Binding of Notch to a DSL ligand results in a conformational change that exposes a cleavage site in the NECD. Enzymatic proteolysis at this site is carried out by a A Disintegrin and Metalloprotease domain (ADAM) family protease. This protein is called Kuzbanian in Drosopihla, [43] [44] sup-17 in C. elegans, [45] and ADAM10 in humans. [46] [47] After proteolytic cleavage, the released NECD is endocytosed into the signal transmitting cell, leaving behind only a small extracellular portion of Notch. This truncated Notch protein can then be recognized by a γ-secretase that cleaves the third site found in the TM domain. [48]


    5 CONCLUSION

    Enthusiastic efforts by researchers around the world over the last two decades have led to the identification of various biological roles of Notch signaling in development, homeostasis, and regeneration in the respiratory system, providing useful clues to elucidate the pathological mechanisms underlying challenging respiratory diseases. These discoveries also prompted us to consider the role of Notch signaling in the conserved molecular machineries dictating development, regeneration and disease in the respiratory system. For example, Notch2 signaling is indispensable in club cell development, and Notch is reactivated in the club cell lineage during airway epithelial regeneration in adulthood. The unique contribution of Notch2 in pathology was determined by studying goblet cell hyperplasia in asthma and COPD. Notch signaling plays a fundamental role in secretory cells of the respiratory system throughout life, from embryonic development to the aging process.

    Many questions remain to be addressed in future studies. For example, the role of Notch signaling in the development of mesenchymal progenitor cells is unknown. The precise control of Notch signaling in regeneration also remains elusive, and a better understating of this process will enable us to completely regulate it and avoid repair failure. Future studies should address these questions to deepen our understanding of the biological functions of Notch signaling, and these findings may shed light on novel treatment targets in various respiratory diseases.



Izohlar:

  1. Arabei

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  2. Rypan

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  3. Tlazohtlaloni

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  4. Thayne

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  5. Eferhard

    Menimcha, siz adashyapsiz. Ishonchim komil. Buni muhokama qilaylik. Meni kechqurun elektron pochta orqali yuboring.

  6. Zolomuro

    Menimcha, siz to'g'ri emassiz. Kirish Biz buni muhokama qilamiz. Menga kechqurun menga yozing, biz gaplashamiz.



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