PAX6

PAX6
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	2CUE, 6PAX
Identifikatori
Aliasi	PAX6
Vanjski ID-jevi	OMIM: 607108 MGI: 97490 HomoloGene: 1212 GeneCards: PAX6
Lokacija gena (čovjek)
Hrom.	Hromosom 11 (čovjek)
Kraj	31,818,062 bp
Lokacija gena (miš)
Hrom.	Hromosom 2 (miš)
Kraj	105,527,709 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• GO:0001948, GO:0016582 vezivanje za proteine; • vezivanje sa DNK; • sequence-specific DNA binding; • GO:0050372 aktivnost sa transferazom ubikvitina; • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific; • GO:0001078, GO:0001214, GO:0001206 DNA-binding transcription repressor activity, RNA polymerase II-specific; • chromatin binding; • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity; • transcription factor binding; • protein kinase binding; • ubiquitin protein ligase binding; • histone acetyltransferase binding; • co-SMAD binding; • R-SMAD binding; • HMG box domain binding; • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding; • RNA polymerase II core promoter sequence-specific DNA binding; • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific;
Ćelijska komponenta	• citoplazma; • jedro; • nukleoplazma; • citosol; • intracellular anatomical structure;
Biološki proces	• eye development; • blood vessel development; • animal organ morphogenesis; • GO:0009373 regulation of transcription, DNA-templated; • glucose homeostasis; • transcription, DNA-templated; • central nervous system development; • response to wounding; • Ćelijska diferencijacija; • cornea development in camera-type eye; • negative regulation of neurogenesis; • Vid; • iris morphogenesis; • multicellular organism development; • neuron fate commitment; • protein ubiquitination; • GO:1901227 negative regulation of transcription by RNA polymerase II; • establishment of mitotic spindle orientation; • cell fate determination; • neuron migration; • GO:0033128 negative regulation of protein phosphorylation; • positive regulation of neuroblast proliferation; • lens development in camera-type eye; • regionalization; • type B pancreatic cell differentiation; • pancreatic A cell development; • GO:0044324, GO:0003256, GO:1901213, GO:0046019, GO:0046020, GO:1900094, GO:0061216, GO:0060994, GO:1902064, GO:0003258, GO:0072212 regulation of transcription by RNA polymerase II; • transcription by RNA polymerase II; • Ježev signalni put; • axonogenesis; • axon guidance; • brain development; • salivary gland morphogenesis; • negative regulation of cell population proliferation; • regulation of asymmetric cell division; • dorsal/ventral axis specification; • anterior/posterior pattern specification; • dorsal/ventral pattern formation; • Regulacija ekspresije gena; • GO:1901313 positive regulation of gene expression; • pallium development; • oligodendrocyte cell fate specification; • cerebral cortex regionalization; • forebrain dorsal/ventral pattern formation; • commitment of neuronal cell to specific neuron type in forebrain; • forebrain-midbrain boundary formation; • telencephalon regionalization; • pituitary gland development; • habenula development; • signal transduction involved in regulation of gene expression; • keratinocyte differentiation; • regulation of cell migration; • positive regulation of epithelial cell differentiation; • forebrain development; • lacrimal gland development; • protein localization to organelle; • eye photoreceptor cell development; • camera-type eye development; • cell fate commitment; • negative regulation of neuron differentiation; • GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • regulation of timing of cell differentiation; • embryonic camera-type eye morphogenesis; • astrocyte differentiation; • negative regulation of epithelial cell proliferation; • regulation of neurogenesis; • retina development in camera-type eye; • cellular response to leukemia inhibitory factor; • negative regulation of neural precursor cell proliferation; • positive regulation of core promoter binding;
	Izvori:Amigo / QuickGO
Ortolozi
	5080
	18508
	ENSG00000007372
	ENSMUSG00000027168
	P26367
	P63015
NM_000280; NM_001127612; NM_001258462; NM_001258463; NM_001258464;
	NM_001258465; NM_001310158; NM_001310159; NM_001310160; NM_001310161; NM_001604
NM_001244198; NM_001244200; NM_001244201; NM_001244202; NM_013627;
	NM_001310144; NM_001310145; NM_001310146
NP_000271; NP_001121084; NP_001245391; NP_001245392; NP_001245393;
	NP_001245394; NP_001297087; NP_001297088; NP_001297089; NP_001297090; NP_001595; NP_001355816; NP_001355817; NP_001355818; NP_001355819; NP_001355820; NP_001355821; NP_001355822; NP_001355823; NP_001355828; NP_001355829; NP_001355830; NP_001355831; NP_001355832; NP_001355833; NP_001355834; NP_001355835; NP_001355836; NP_001355837; NP_001355838; NP_001355839; NP_001355840; NP_001355841; NP_001355842; NP_001355843; NP_001355844; NP_001355845; NP_001355846; NP_001355847; NP_001355848; NP_001355849; NP_001355850; NP_001355851; NP_001355852; NP_001355853; NP_001355854; NP_001355855; NP_001355856; NP_001355857; NP_001355858; NP_001355859
NP_001231127; NP_001231129; NP_001231130; NP_001231131; NP_001297073;
	NP_001297074; NP_001297075; NP_038655
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Upareni kutijski protein Pax-6, znan i kao aniridijski protein tip II (AN2) ili okulorombin, je protein koji je kod ljudi kodiran genom PAX6.^[5]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 422 aminokiseline, a molekulska težina 46.683 Da.^[6]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MQNSHSGVNQ	LGGVFVNGRP	LPDSTRQKIV	ELAHSGARPC	DISRILQVSN
GCVSKILGRY	YETGSIRPRA	IGGSKPRVAT	PEVVSKIAQY	KRECPSIFAW
EIRDRLLSEG	VCTNDNIPSV	SSINRVLRNL	ASEKQQMGAD	GMYDKLRMLN
GQTGSWGTRP	GWYPGTSVPG	QPTQDGCQQQ	EGGGENTNSI	SSNGEDSDEA
QMRLQLKRKL	QRNRTSFTQE	QIEALEKEFE	RTHYPDVFAR	ERLAAKIDLP
EARIQVWFSN	RRAKWRREEK	LRNQRRQASN	TPSHIPISSS	FSTSVYQPIP
QPTTPVSSFT	SGSMLGRTDT	ALTNTYSALP	PMPSFTMANN	LPMQPPVPSQ
TSSYSCMLPT	SPSVNGRSYD	TYTPPHMQTH	MNSQPMGTSG	TTSTGLISPG
VSVPVQVPGS	EPDMSQYWPR	LQ

Specijska distribucija

Izmjene proteina Pax6 rezultiraju sličnim fenotipskim promjenama morfologije i funkcije oka kod širokog spektra vrsta.

Funkcija proteina PAX6 je visoko konzerviranana kod bilaterijskih vrsta. Naprimjer, mišji PAX6 može pokrenuti razvoj oka u Drosophila melanogaster. Osim toga, mišji i ljudski PAX6 imaju identične aminokiselinske sekvence.^[7]

Genomska organizacija lokusa PAX6 razlikuje se među vrstama, uključujući broj i distribuciju egzona, cis-regulatornih elemenata i mjesta početka transkripcije s,^[8]^[9] iako se većina elemenata na razred Vertebrata međusobno poravnavaju.^[10]^[11] Prvi rad na organizaciji genoma izveden je na prepelicama, ali je slika lokusa miša najcjelovitija do sada. Sastoji se od tri potvrđena promotora (P0, P1, Pα), 16 egzona i najmanje šest pojačivača. 16 potvrđenih egzona numerirano je od 0 do 13 sa dodacima egzona α koji se nalazi između egzona 4 i 5, i alternativno prerađenim egzonom 5a. Svaki promotor je povezan sa svojim proksimalnim egzonom (egzon 0 za P0, egzon 1 za P1), što rezultira transkriptima koji su alternativno prerađeni u 5' neprevedenoj regiji.^[12] Po dogovoru, egzoni za ortologe iz drugih vrsta imenuju se u odnosu na numeriranje čovjeka/miša, sve dok je organizacija razumno dobro konzervirana.^[11]

Od četiri Pax6 ortologa u Drosophila smatra se da proizvodi gena bez oka (ey) i bezoki blizanac (toy) dijele funkcionalnu homologiju sa kanonskom izoformom Pax6 kičmenjaka, dok genski proizvodi eyegone (eyg) i twin of eyegone (toe) dijele funkcionalnu homologiju sa izoformom Pax6 (5a) kičmenjaka. Bezoke oči i oči s okom nazvane su po odgovarajućim mutiranim fenotipovima. Ovi paralozi također igmju ulogu u razvoju cijelog očno-antenskog diska, a posljedično i u formiranju glave, a^[13] toy pozitivno regulira ekspresiju gena ey.^[14]

Funkcija

PAX6 je član porodice gen Pax, koja je odgovorna za prijenos genetičkih informacija koje će kodirati protein Pax-6. Djeluje kao gen "glavne kontrole" za razvoj očiju i drugih čulnih organa, određenih neuronskih i epidermnih tkiva, kao i drugih homolognih struktura, obično izvedenih iz ektoderma svih tkiva . Međutim, prepoznato je da je niz gena neophodan za razvoj oka, pa stoga izraz "glavni kontrolni gen" može biti netačan.^[15] Pax-6 se eksprimira kao faktor transkripcije kada neuronski ektoderm primi kombinaciju slabih soničnog ježa (SHH) i jakih TGF-beta) signalnih gradijenata. Ekspresija se prvi put vidi u prednjem, stražnjem, glavnom dijelu ektoderma i leđnoj moždini, a zatim u srednjem mozgu. Ovaj transkripcijski faktor je najzapaženiji po svojoj upotrebi u međuspecijski induciranoj ekspresiji ektopijskih očiju i od medicinske je važnosti jer heterozigotni mutanti proizvode širok spektar očnih defekata kao što je aniridija kod ljudi.^[16]

Pax6 služi kao regulator u koordinaciji i formiranju obrazaca potrebnih za uspješnu diferencijaciju i proliferaciju, osiguravajući da se procesi neurogeneze i okulogeneze uspješno provode. Kao transkripcijski faktor, Pax6 djeluje na molekulnom nivou u signalizaciji i formiranju centralnog nervnog sistema. Karakteristični upareni DNK vezujući domen Pax6 koristi dva domena koji se vezuju za DNK, upareni domen (PD) i upareni tip homeodomena (HD). Ovi domeni funkcioniraju odvojeno pomoću Pax6 za izvođenje molekulne signalizacije, koja regulira posebne funkcije Pax6. Primjer toga leži u regulatornom uključivanju HD-a u formiranju leće i retine tokom okulogeneze, za razliku od molekulnih mehanizama kontrole izloženih na obrascima neurogeneze u razvoju mozga pomoću PD. HD i PD domeni djeluju u uskoj koordinaciji, dajući Pax6 njegovu multifunkcionalnu prirodu u usmjeravanju molekulske signalizacije u formiranju CNS-a. Iako su mnoge funkcije Pax6 poznate, molekuldki mehanizmi ovih funkcija ostaju uglavnom neriješeni.^[17] High-throughput studies uncovered many new target genes of the Pax6 transcription factors during lens development.^[18] Oni uključuju aktivator transkripcije BCL9, nedavno identificiran, zajedno s Pygo2, kao nizvodne efekte funkcija Pax6.^[19]

Izoforme

Lokus PAX6 kikmenjaka kodira najmanje tri različite proteinske izoforme, a to su kanonski PAX6, PAX6 (5a) i PAX6 (ΔPD). Kanonski protein PAX6 sadrži N-terminalni upareni domen, povezan regijom veze s uparenom homeodomenom, i C-terminalni domen bogat prolinom/serinom/treoninom (P/S/T). Upareni domen i domaćinski domen uparenog tipa imaju aktivnosti vezivanja za DNK, dok domen bogat P/S/T oma funkciju aktivacije. PAX6 (5a) je proizvod alternativno prerađenog egzona 5a koji rezultira insercijom 14 ostataka u upareni domen, što mijenja specifičnost ove aktivnosti vezivanja DNK. Nukleotidna sekvenca koja odgovara linkerskoj regiji kodira skup od tri alternativna kodona za početak translacije. iz kojih potiče treća izoforma PAX6. Zajedno poznate kao PAX6 (ΔPD) ili uparene izoforme, ova tri genska proizvoda nemaju upareni domen. Upareni proteini imaju molekulsku težinu od 43, 33 ili 32 kDa, ovisno o određenom početnom kodonu koji se koristi. Funkcija transaktivacije PAX6 pripisuje se C-terminalnom domenu bogatom P/S/T, promjenjive dužine, koja se proteže na 153 ostatka u ljudskim i mišjim proteinima.

Napredovanje istraživanja u ovom području moglo bi nas dovesti do boljeg razumijevanja složenosti koja se vidi u neuronskom razvoju i možda će jednog dana uspjeti rasti tkivo oka in vitro. Tokom razvoja embriona, gen PAX6, pronađen na hromosomu 2, može se vidjeti eksprimiran u više ranih struktura kao što su leđna moždina, zadnji mozak, prednji mozak i oči.^[20] Mutacije gena PAX6 kod sisarskih vrsta mogu imati drastičan učinak na fenotip organizma. To se može vidjeti kod miševa koji sadrže homozigotne mutacije 422-aminokiselinskih transkripcijskih faktora, kodiranih PAX6 u kojima ne razvijaju oči ili nosne šupljine nazvane mišje „male oči“ (PAX10^sey/sey).^[20]^[21] Delecija PAX6 inducira iste abnormalne fenotipove koji ukazuju na to da mutacije uzrokuju gubitak proteina. PAX6 je bitan za stvaranje retine, leće i rožnjače, zbog njegove uloge u ranoj determinaciji ćelija pri formiranju prekursora ovih struktura, poput optičkog mjehurića i nadređenog površinskog ektoderm.^[21] PAX10 mutacije također ometaju razvoj nosne šupljine, zbog sličnih prekursorskih struktura koje u malih očnih miševa ne eksprimiraju PAX10-ovu iRNK.^[22] Miševi kojima nedostaje bilo koji funkcionalni pax6 počinju se fenotipski razlikovati od normalnih mišjih embrija oko 9. do 10. dana trudnoće.^[23] Potpuno razjašnjenje preciznih mehanizama i molekulskih komponenti pomoću kojih gen PAX6 utiče na razvoj oka, nazalnog i centralnog nervnog sistema još se istražuje, međutim, proučavanje PAX6 je donijelo više razumijevanja za razvoj i genetičke složenosti ovih tjelesnih sistema sisara.

Klinički značaj

Eksperimenti na miševima pokazuju da nedostatak Pax-6 dovodi do smanjenja veličine mozga, abnormalnosti strukture mozga dovode do autizma, nedostatka stvaranja šarenice ili tanke rožnjače. Nokaut-eksperimenti proizveli su fenotipove bez očiju koji su potvrdili uloge gena u razvoju oka.^[16]

Također pogledajte

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000007372 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000027168 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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^ Walcher T, Xie Q, Sun J, Irmler M, Beckers J, Öztürk T, Niessing D, Stoykova A, Cvekl A, Ninkovic J, Götz M (mart 2013). "Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation". Development. 140 (5): 1123–36. doi:10.1242/dev.082875. PMC 3583046. PMID 23404109.
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^ Cantù C, Zimmerli D, Hausmann G, Valenta T, Moor A, Aguet M, Basler K (septembar 2014). "Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse lens development". Genes & Development. 28 (17): 1879–84. doi:10.1101/gad.246140.114. PMC 4197948. PMID 25184676.
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Vanjski linkovi

PAX6 protein na US National Library of Medicine Medical Subject Headings (MeSH)
GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview
GeneReviews/NCBI/NIH/UW entry on Aniridia
OMIM entries on Aniridia
Gene Expression Patterns^{[mrtav link]} from the Allen Brain Atlases
P26367

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000007372 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000027168 - Ensembl, maj 2017

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