Koštanomorfogenetski protein 4

Koštanomorfogenetski protein 4
Identifikatori
Aliasi	BMP4
Vanjski ID-jevi	OMIM: 112262 MGI: 88180 HomoloGene: 7247 GeneCards: BMP4
Lokacija gena (miš)
Hrom.	Hromosom 14 (miš)
Kraj	46,628,126 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• heparin binding; • cytokine activity; • co-receptor binding; • transforming growth factor beta receptor binding; • growth factor activity; • BMP receptor binding; • GO:0001948, GO:0016582 vezivanje za proteine; • chemoattractant activity;
Ćelijska komponenta	• extracellular region; • Vanćelijsko; • endoplasmic reticulum lumen;
Biološki proces	• embryonic skeletal system morphogenesis; • negative regulation of T cell differentiation in thymus; • germ cell development; • skeletal system development; • mesenchymal cell differentiation involved in renal system development; • cardiac septum development; • ureteric bud development; • positive regulation of protein phosphorylation; • renal system process; • positive regulation of endothelial cell differentiation; • negative regulation of immature T cell proliferation in thymus; • bud elongation involved in lung branching; • tendon cell differentiation; • anatomical structure formation involved in morphogenesis; • ureter epithelial cell differentiation; • negative regulation of cell cycle; • mesenchymal to epithelial transition involved in metanephros morphogenesis; • trachea development; • post-embryonic development; • monocyte differentiation; • specification of ureteric bud anterior/posterior symmetry by BMP signaling pathway; • blood vessel endothelial cell proliferation involved in sprouting angiogenesis; • BMP signaling pathway involved in renal system segmentation; • cranial suture morphogenesis; • mesonephros development; • odontogenesis of dentin-containing tooth; • telencephalon regionalization; • negative regulation of chondrocyte differentiation; • blood vessel development; • negative regulation of mitotic nuclear division; • Angiogeneza; • prostate gland morphogenesis; • positive regulation of ERK1 and ERK2 cascade; • smooth muscle tissue development; • BMP signaling pathway involved in heart induction; • negative regulation of epithelial cell proliferation; • tissue development; • metanephric collecting duct development; • inner ear receptor cell differentiation; • mesodermal cell fate determination; • metanephros development; • type B pancreatic cell development; • regulation of pathway-restricted SMAD protein phosphorylation; • negative regulation of cell population proliferation; • steroid hormone mediated signaling pathway; • mammary gland formation; • positive regulation of collagen biosynthetic process; • renal system development; • negative regulation of myoblast differentiation; • cell fate commitment; • common-partner SMAD protein phosphorylation; • glomerular visceral epithelial cell development; • SMAD protein signal transduction; • ossification; • Nefrogeneza; • lung development; • ureter smooth muscle cell differentiation; • embryonic digit morphogenesis; • epithelial-mesenchymal cell signaling; • negative regulation of thymocyte apoptotic process; • mesenchymal cell differentiation involved in kidney development; • negative regulation of cell death; • regulation of odontogenesis of dentin-containing tooth; • BMP signaling pathway involved in ureter morphogenesis; • mesenchymal cell proliferation involved in ureteric bud development; • smooth muscle cell differentiation; • lymphoid progenitor cell differentiation; • epithelium development; • GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated; • deltoid tuberosity development; • negative regulation of prostatic bud formation; • heart development; • telencephalon development; • branching involved in ureteric bud morphogenesis; • positive regulation of kidney development; • cartilage development; • embryonic limb morphogenesis; • negative regulation of MAP kinase activity; • positive regulation of cartilage development; • lens induction in camera-type eye; • positive regulation of neuron differentiation; • branching involved in prostate gland morphogenesis; • regulation of protein import into nucleus; • positive regulation of cell differentiation; • erythrocyte differentiation; • Ježev signalni put; • camera-type eye development; • secondary heart field specification; • negative regulation of phosphorylation; • regulation of smooth muscle cell differentiation; • regulation of cell fate commitment; • regulation of branching involved in prostate gland morphogenesis; • Ćelijska diferencijacija; • positive regulation of branching involved in lung morphogenesis; • chondrocyte differentiation; • regulation of cartilage development; • organ induction; • positive regulation of epithelial cell proliferation; • epithelial cell proliferation involved in lung morphogenesis; • negative regulation of cell proliferation involved in heart morphogenesis; • negative regulation of apoptotic process; • positive regulation of ossification; • endochondral ossification; • regulation of smooth muscle cell proliferation; • regulation of morphogenesis of a branching structure; • BMP signaling pathway; • macrophage differentiation; • negative regulation of metanephric comma-shaped body morphogenesis; • embryonic skeletal system development; • mesenchymal cell proliferation involved in ureter development; • osteoblast differentiation; • hematopoietic progenitor cell differentiation; • positive regulation of BMP signaling pathway; • Regulacija ekspresije gena; • embryonic cranial skeleton morphogenesis; • dorsal/ventral neural tube patterning; • lung alveolus development; • positive regulation of protein binding; • anterior/posterior axis specification; • GO:0045996 negative regulation of transcription, DNA-templated; • positive regulation of epidermal cell differentiation; • branching morphogenesis of an epithelial tube; • trachea formation; • specification of animal organ position; • negative regulation of glomerular mesangial cell proliferation; • positive regulation of smooth muscle cell proliferation; • intermediate mesodermal cell differentiation; • pulmonary artery endothelial tube morphogenesis; • pituitary gland development; • positive regulation of cell death; • lung morphogenesis; • positive regulation of endothelial cell proliferation; • bud dilation involved in lung branching; • positive regulation of cardiac muscle fiber development; • negative regulation of striated muscle tissue development; • positive regulation of cell migration; • negative regulation of branch elongation involved in ureteric bud branching by BMP signaling pathway; • BMP signaling pathway involved in nephric duct formation; • positive regulation of pathway-restricted SMAD protein phosphorylation; • negative regulation of mesenchymal cell proliferation involved in ureter development; • mesoderm formation; • cellular response to growth factor stimulus; • glomerular capillary formation; • bronchus development; • positive regulation of endothelial cell migration; • multicellular organism development; • negative regulation of metanephric S-shaped body morphogenesis; • neural tube closure; • vasculature development; • embryonic morphogenesis; • protein localization to nucleus; • positive regulation of apoptotic process; • embryonic skeletal joint morphogenesis; • regulation of cell differentiation; • negative regulation of branching involved in ureteric bud morphogenesis; • mesodermal cell differentiation; • neuron fate commitment; • forebrain development; • cloacal septation; • bone development; • camera-type eye morphogenesis; • positive regulation of SMAD protein signal transduction; • negative regulation of glomerulus development; • embryonic hindlimb morphogenesis; • positive chemotaxis; • outflow tract morphogenesis; • odontogenesis; • GO:1901227 negative regulation of transcription by RNA polymerase II; • epithelial to mesenchymal transition involved in endocardial cushion formation; • cardiac jelly development; • cellular response to BMP stimulus; • positive regulation of osteoblast differentiation; • epithelial tube branching involved in lung morphogenesis; • cardiac muscle cell differentiation; • apoptotic process involved in endocardial cushion morphogenesis; • muscular septum morphogenesis; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • positive regulation of bone mineralization; • cardiac right ventricle morphogenesis; • outflow tract septum morphogenesis; • membranous septum morphogenesis; • aortic valve morphogenesis; • pulmonary valve morphogenesis; • endocardial cushion development; • endoderm development; • coronary vasculature development; • BMP signaling pathway involved in heart development; • pharyngeal arch artery morphogenesis; • positive regulation of cell proliferation involved in outflow tract morphogenesis; • negative regulation of extrinsic apoptotic signaling pathway; • regulation of pri-miRNA transcription by RNA polymerase II; • positive regulation of production of miRNAs involved in gene silencing by miRNA; • Posttranslacione modifikacije; • GO:1901313 positive regulation of gene expression; • positive regulation of epithelial to mesenchymal transition; • positive regulation of cardiac neural crest cell migration involved in outflow tract morphogenesis; • regulation of signaling receptor activity; • positive regulation of cell population proliferation; • negative regulation of gene expression; • negative regulation of pri-miRNA transcription by RNA polymerase II; • regulation of apoptotic process; • regulation of MAPK cascade; • cell development; • growth;
	Izvori:Amigo / QuickGO
Ortolozi
	652
	12159
	ENSG00000125378
	ENSMUSG00000021835
	P12644
	P21275
	NM_001202; NM_130850; NM_130851
	NM_007554; NM_001316360
NP_001193; NP_570911; NP_001334841; NP_001334842; NP_001334843;
	NP_001334844; NP_001334845; NP_001334846; NP_570912
	NP_001303289; NP_031580
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Koštanomorfogenetski protein 4 jest protein koji je kod ljudi kodiran genom BMP4 sa hromosoma 14, sekvenca 14q22-q23.^[4]^[5]

Otkriće

Koštanomorfogenetski proteini su prvobitno identifikovani sposobnošću demineralizovanog ekstrakta kostiju da indukuje endohrskavičnu osteogenezu in vivo na vanskeletnom mjestu.

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je aminokiselina, a molekulska težina Da.^[5]

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
MIPGNRMLMV	VLLCQVLLGG	ASHASLIPET	GKKKVAEIQG	HAGGRRSGQS
HELLRDFEAT	LLQMFGLRRR	PQPSKSAVIP	DYMRDLYRLQ	SGEEEEEQIH
STGLEYPERP	ASRANTVRSF	HHEEHLENIP	GTSENSAFRF	LFNLSSIPEN
EVISSAELRL	FREQVDQGPD	WERGFHRINI	YEVMKPPAEV	VPGHLITRLL
DTRLVHHNVT	RWETFDVSPA	VLRWTREKQP	NYGLAIEVTH	LHQTRTHQGQ
HVRISRSLPQ	GSGNWAQLRP	LLVTFGHDGR	GHALTRRRRA	KRSPKHHSQR
ARKKNKNCRR	HSLYVDFSDV	GWNDWIVAPP	GYQAFYCHGD	CPFPLADHLN
STNHAIVQTL	VNSVNSSIPK	ACCVPTELSA	ISMLYLDEYD	KVVLKNYQEM
VVEGCGCR

Struktura proteina

Dajući aktivni karboksi-terminalni peptid od 116 ostataka, ljudski BMP4 se inicijalno sintetizira kao preprotein od 40% ostatka koji se cijepa nakon translacije. BMP4 ima sedam ostataka koji su konzervirani i glikozilirani.^[6] Monomeri se drže disulfidnim mostovima i tri para cisteinskih aminokiselina. Ova konformacija naziva se "cistinski čvor". BMP4 može formirati homodimere ili heterodimere sa sličnim BMPS. Jedan primjer za to je BMP7. Ova sposobnost stvaranja homodimera ili heterodimera daje mogućnost veće osteoinduktivne aktivnosti nego samog BMP4.^[7] Još se ne zna mnogo o tome kako BMPS stupa u interakciju sa vanćelijskim matriksom. Isto tako, malo se zna o putevima koji zatim razgrađuju BMP4.

Funkcija

BMP4 je član porodice koštanomorfogenetskih proteina koja je dio natporodice transformirajućih faktora rasta-beta. Natporodica uključuje velike porodice faktora rasta i diferencijacije. BMP4 je evolucijski visoko konzerviran. Nalazi u ranom embrionskom razvoju u ventralnoj marginalnoj zoni i u očima, srčanoj krvi i ušnoj vezikuli.^[8]

BMP4 također ograničava stepen do kojeg dolazi do nervne diferencijacije u embrionima ksenopusa izazivanjem epiderme. Mogu pomoći u indukciji bočnih karakteristika u somitima. Somiti su potrebni za razvoj struktura kao što su mišići udova. BMP4 pomaže u oblikovanju glave u razvoju iako izaziva apoptoze ćelija nerevnog grebena ćelije; ovo se dešava u zadnjem mozgu.^[9]

Kod odraslih, BMP4 je važan za neurogenezu (tj. stvaranje novih neurona) koja se javlja tokom života u dvije neurogene niše mozga, dentatni girus hipokampusa i subventrikulskoj zoni (SVZ) uz bočne komore. U ovim nišama, novi neuroni se kontinuirano stvaraju iz matičnih ćelija. U stvari, pokazalo se da u dentatnom girusu BMP4 održava nervne matične ćelije u mirovanju, čime se sprečava iscrpljivanje pula matičnih ćelija.^[10] U SVZ, BMP posredovana signalizacija putem Smad4 je potrebna za pokretanje neurogeneze iz odraslih nervnih matičnih ćelija i potiskivanje alternativne sudbine oligodendrogliogeneze.^[11] Štaviše, pokazalo se da u SVZ BMP4 ima diferencijativni učinak, jer sprečava defekt terminalne diferencijacije u SVZ neurosferama gdje je deletira gen Tis21/BTG2 –x potreban za terminalnu diferencijaciju.^[12] Tis21 is a positive regulator of BMP4 expression in the SVZ.^[12]

BMP4 je važan za metabolizam kostiju i hrskavice. BMP4 signalizacija je pronađena u formiranju ranih mezodermnih i zametnih ćelija. Regulacija pupoljaka ekstremiteta i razvoj pluća, jetre, zuba i mezenhimskih ćelija lica su druge važne funkcije koje se pripisuju signalizaciji BMP4-a.^[13] Na formiranje prstiju utiče BMP4, zajedno sa drugim BMP signalima. Interdigitalni mezenhim pokazuje BMP4, koji sprečava apoptozu regije.^[14] Formiranje zuba se oslanja na ekspresiju BMP4, koja indukuje Msx 1 i 2. Ovi faktori transkripcije pretvaraju formirani zub da postane i sjekutić.

BMP4 također ima važnu ulogu u masnom tkivu: neophodan je za adipogenezu bijelog masnog tkiva i promovira diferencijaciju adipocita.^[15] Osim toga, važan je i za smeđu mast, gdje indukuje UCP1, povezan sa termogenezom bez drhtanja.^[15]

Izlučivanje BMP4 pomaže u diferencijaciji pupoljka uretera u mokraćovod.^[16]

BMP4 antagonizira tkivo organizatora i eksprimira se u ranom razvoju u tkivu ektoderma i mezoderma. Nakon gastrulacije, transkripcija BMP4 je ograničena na ventrolateralnu marginalnu zonu, zbog inhibicije sa dorzalne strane embriona u razvoju. BMP4 pomaže u ventralizaciji mezoderma, koji vodi formiranje dorzalno-ventralne ose. U rodu Xenopus, za BMP4 otkriveno je da pomaže u formiranju krvi i krvnih ostrva.^[17]

BMP4, prvobitno eksprimiran u epidermi, tokom formiranja nervne cijevi, nalazi se u krovnoj ploči. Gradijent BMP signalizacije nalazi se u suprotnosti sa gradijentom zvučnog ježa. Ova ekspresija BMP4 oblikuje dorzalne neurone.^[18]

BMP4, zajedno sa FGF2, promoviše diferencijaciju matičnih ćelija u mezodermne linije. Nakon diferencijacije, ćelije tretirane BMP4 i FGF2 općenito proizvode veće količine osteogene i hondorgene diferencijacije nego netretirane matične ćelije.^[19] Također, u kombinaciji sa FGF2 može proizvesti progenitorne ćelije štitne žlijezde iz pluripotentnih matičnih ćelija kod miševa i ljudi.^[20]

Pokazalo se da BMP4 indukuje ekspresiju gena porodice Msx, za koju se vjeruje da je dio formiranja hrskavice iz somitskog mezoderma.^[21]

BMP4, parakrini faktor rasta, pronađen je kod pacovskih jajnika. BMP4, zajedno sa BMP7, reguliše rani razvoj folikula jajnika i prelazak iz primordijalnog u primarni folikul. Osim toga, pokazalo se da inhibicija BMP4 antitijelima smanjuje ukupnu veličinu jajnika. Ovi rezultati pokazuju da BMP4 može pomoći u preživljavanju i prevenciji apoptoze kod oocita.^[13]

Kod ptica pokazalo se da BMP4 utiče na veličinu kljuna Darwinove zebe. Male količine BMP4 su u korelaciji sa niskom dubinom i širinom kljuna. Suprotno tome, visoka ekspresija BMP4 stvara veliku dubinu i širinu kljuna. Genetička regulacija BMP4 pruža osnovu za prirodnu selekciju u ptičjim kljunovima.^[22]

Inhibicija

Inhibicija BMP4 signala (putem hordina, nogina ili folistatina) uzrokuje da se ektoderm diferencira u nervnu ploču. Ako ove ćelije takođe primaju signale od FGF, one će se diferencirati u kičmenu moždinu; u nedostatku FGF ćelije postaju moždano tkivo.

Dok prekomjerna ekspresija BMP4 može dovesti do ventralizacije, inhibicija s dominantnim negativnim uticajem može rezultirati potpunom dorzalizacijom embrija ili formiranjem dvije osovine.^[23]

Važno je napomenuti da su miševi kod kojih je BMP4 inaktiviran obično uginuli tokom gastrulacija. Smatra se da bi inaktivacija ljudskog BMP4 vjerovatno imala isti efekat. Međutim, mutacije koje su suptilne kod ljudi mogu imati i suptilne fenotipske efekte.

Izoforme

Opisana je alternativna preradaalternativno u 5' neprevedenom regionu ovog gena i opisane su tri varijante transkripta, od kojih sve kodiraju identičan protein.^[24]

Molekulski mehanizmi

BMP4, kao član porodice transformirajućih faktora rasta-β (TGF-β), vezuje se za dva različita tipa receptora serin-treonin kinaze, poznatih kao BMPR1 i BMPR2.^[25] Dolazi do prijenosa signala preko ovih receptora putem Smad-a i mapiraju kinazne puteve da bi izvršili transkripciju svojih ciljnih gena. Da bi došlo do transdukcije signala, oba receptora moraju biti funkcionalna. BMP se može vezati za BMPR2 bez BMPR1; međutim afinitet se značajno povećava u prisustvu oba receptora. BMPR1 je transfosforiliran preko BMPR2 koji indukuje nizvodnu signalizaciju unutar ćelije, utičući na transkripciju.^[25]

Signalni put Smad

Za transdukciju signala, receptori porodice TGF-β najčešće koriste Smadov signalni put.^[25] Tip 2 receptora odgovorni su za aktiviranje tipa 1 receptora, gdje njihova funkcija uključuje fosforilacije R-Smada (Smad-1, Smad-5, Smad-8). Nakon fosforilacije, javlja se formiranje R-SMAD kompleksa u sprezi sa zajedničkim partnerom Smad (ko-Smad), gdje migrira u nukleus. Signalizacija ovog puta regulirana je malim molekulskim inhibitorom, poznatim kao doruzomorfin koji sprječava nizvodne efekte R-smada.^[25]

Mapa signalnih kinaznih puteva (MAPK)

Mitogenom aktivirane proteinske kinaze (MAPK) prolaze kroz fosforilaciju putem signalne kaskade, gdje MAPKKK fosforilira i aktivira MAPKK i MAPKK fosforilira i aktivira MAPK, što zatim inducira unutarćelijski odgovor.^[26] Aktivacija MAPKKK je putem interakcije uglavnom GTPaza ili druge grupe proteinskih kinaza. TGF-β receptori induciraju MAPK signalne puteve ERK, JNK i p38.^[26] Poznato je da BMP4 aktivira ERK, JNK i p38 MAPK signalne puteve, dok je otkriveno da djeluje nezavisno od Smad puteva signalizacije, uglavnom su aktivni u sprezi sa Smadom.^[27] Aktivacija ERK i JNK puteva djeluje na fosforilaciju Smada i stoga reguliše njegovu aktivaciju. Pored toga, MAPK putevi mogu biti u mogućnosti da direktno utiču na transkripcijske faktore u interakciji sa Smadom, preko JNK ili p38 supstrata koji indukuje konvergenciju dva signalna puta. Zapaženo je da se ova konvergencija uglavnom sastoji od kooperativnog ponašanja; međutim, postoje dokazi koji ukazuju na to da se oni ponekad mogu međusobno suprotstaviti. Nadalje, ravnoteža koja postoji između direktne aktivacije ovih signalnih puteva ima značajan utjecaj na TGF-β inducirane ćelijske odgovore.^[27]

Generiranje matičnih ćelija trofoblasta iz kunićevih embrionske matične ćelije sa BMP4-pone.0017124.s005

Klinički značaj

Povećanje ekspresije BMP4 povezano je sa raznim bolestima kostiju, uključujući nasljedni poremećaj fibrodysplasia ossificans progressiva.^[28] Postoje jaki dokazi iz studija sekvenciranja gena kandidata uključenih u rascjep da mutacije u genu koštanomorfogenetskog proteina 4 (BMP4) mogu biti povezane u patogenezi rascjepa usne i/ili nepca.^[29]

Razvoj očiju

Oči su neophodne organizmima, posebno kopnenim kičmenjacima, da posmatraju plijen i prepreke; ovo je ključno za njihov opstanak. Formiranje očiju počinje kao očne vezikule i sočiva izvedena iz neuroektoderma. Poznato je da koštanomorfogenetski proteini stimulišu formiranje očnih sočiva.

Tokom ranog razvoja očiju, formiranje očnih vezikula je bitno kod miševa i BMP4 je snažno izražen u očnoj vezikuli i slabo u okolnom mezenhimu i površinskom ektodermu. Ovaj koncentracijski gradijent BMP4 u očnoj vezikuli je kritičan za indukciju sočiva. Dr. Furuta i dr. Hogan otkrili su da ako se laserski inducira mutacija na embrionima miševa nastaje BMP4 homozigotna nulta mutacija, zbog koje ovaj embrion neće razviti sočivo. Također su uradili in situ hibridizacija gena BMP4, pokazujući zelenu boju i Sox2 gen u crvenoj za koji su mislili da je također uključen u formiranje sočiva. Nakon što su izvršili ove dvije in situ hibridizacije u embrionima miševa, otkrili su da se i zelena i crvena boja nalaze u optičkoj vezikuli mišjih embriona. Ovo je pokazalo da su BMP4 i Sox2 eksprimirani na pravom mjestu u pravo vrijeme očnih vezikula i dokazuju da imaju neke bitne funkcije za indukciju sočiva. Nadalje, izvršili su naknadni eksperiment ubrizgavanjem BMP4 u BMP4 homozigotni mutantni embrioni i spasili formiranje sočiva. Ovo ukazuje da je BMP4 definitivno potreban za formiranje sočiva. Međutim, također su otkrili da se neki od mutiranih miševa ne mogu spasiti. Kasnije su otkrili da tim mutantima nedostaje Msx 2 koji se aktivira BMP4. Mehanizam koji su predvidjeli bio je da će BMP4 aktivirati Msx 2 u očnoj vezikuli i da su zajednička kombinacija koncentracije BMP4 i Msx2 i aktivni Sox2 i Sox2 neophodni za diferencijaciju sočiva.^[30]

Injection of Noggin into lens fiber cells in mice significantly reduces the BMP4 proteins in the cells. This indicates that Noggin is sufficient to inhibit the production of BMP4. Moreover, another inhibitor protein, Alk6 was found that blocked the BMP4 from activating the Msx2 which stopped lens differentiation .^[31] However, there are still a lot of unknown about the mechanism of inhibition on BMP4 and downstream regulation of Sox2. In the future, researchers are aiming to find out a more complete pathway of whole eye development and hoping one day, they can find a way to cure some genetic caused eye diseases.

Gubitak kose

Gubitak kose/dlake, poznat kao alopecija uzrokovan je promjenom morfologije folikula dlake i njenim ciklusom na abnormalan način.^[32] Ciklusi folikula dlake su ciklusi rasta, ili anagen, regresije ili katagen, i mirovanja ili telogen.^[33] Kod sisara, recipročne epitelne i mezenhimske interakcije kontrolišu razvoj dlake. Geni kao što su BMP4 i BMP2 su oba aktivni unutar dlakinih prekursora. Konkretno, BMP4 nalazi se u dermnoj papili. BMP4 je dio signalne mreže koja kontrolira razvoj kose. Potreban je za indukciju biohemijskih puteva i signalizaciju za regulaciju diferencijacije osovine dlake u anagenom dlakinom folikulu. Ovo se postiže kontrolom ekspresije transkripcijskih faktora koji regulišu diferencijaciju dlaka. Međutim, još uvijek je nejasno gdje BMP djeluju unutar genetičke mreže. Signalizacija bmp4 može potencijalno kontrolirati ekspresiju terminalnih diferencijacijskih molekula kao što su keratini. Pokazalo se da i drugi regulatori kontrolišu razvoj dlakinog folikula. HOXC13 i FOXN1 smatraju se važnim regulatorima jer eksperimenti s gubitkom funkcije pokazuju narušenu diferencijaciju osovine dlake koja ne ometa formiranje folikula dlake.^[34]

Kada se BMP4 eksprimira ektopijski, kod transgenih miševa inhibira se vanjska ovojnica korijena dlakinog folikula (ORS) i proliferacija ćelijskog matriksa. BMP4 takođe aktivira ekspresije gena za dlakin keratin, napominjući da je BMP4 važan u diferencijaciji vlasi. Nogin, poznati inhibitor BMP4, nalazi se u ćelijama dlakinog matriksa. Drugi važni faktori koje treba uzeti u obzir u razvoju dlake su ekspresija Shh (sonični jež), BMP7, BMP2, WNT i β-katenin jer su oni potrebni u ranoj fazi morfogeneze.^[35]

Ostali geni koji mogu inhibirati BMP4 ili stupiti u interakciju s BMP4 su nogin, folistatin i gremlin, koji su svi eksprimirani u folikulima dlake u razvoju.^[36] Kod miševa kod kojih nedostaje nogin, ima manje dlakinih folikula nego kod normalnog miša i razvoj folikula je inhibiran. U kokošijim embrionima pokazano je da ektopijsko eksprimirani nogin proizvodi uvećane folikule, a BMP4 signalizacija pokazuje potisnutu sudbinu plakoda u obližnjim ćelijama.^[7] Tokom eksperimenata in vivo, pokazalo se da nogin je također indukuje rast dlaka na postneonatusnoj koži.^[37]

BMP4 je važna komponenta bioloških puteva koji su uključivali regulaciju diferencijacije osovine dlake unutar anagenog dlakinog folikula. Najjači nivoi ekspresiranog BMP4 nalaze se unutar medule, ćelija dlake, distalnog matriksa dlake i potencijalnih prekursora kutikula. Dva glavna načina koji BMP4 inhibiraju ekspresiju dlake su ograničavanje ekspresije faktora rasta u matriksu dlake i antagonizam između signalizacije rasta i diferencijacije.^[35]

Putevi koji regulišu formiranje folikula dlake i rast dlake ključni su u razvoju terapijskih metoda za stanja opadanja kose. Takva stanja uključuju razvoj novih folikula, promjenu oblika karakteristika postojećih folikula i promjenu rasta dlake u postojećim dlakinim folikulima. Nadalje, BMP4 i put kroz koji djeluje mogu pružiti terapeutske ciljeve za prevenciju gubitka kose.^[33]

Reference

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Vanjski linkovi

BMPedia - the Bone Morphogenetic Protein Wiki^{[trajno mrtav link]}
BMP4 lokacija ljudskog genoma UCSC Genome Browser.

BMP4 detalji ljudskog genoma u UCSC Genome Browser.

[refGRCm38Ensembl-1] GRCm38: Ensembl release 89: ENSMUSG00000021835 - Ensembl, maj 2017

[2] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[3] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid7558046-4] van den Wijngaard A, Weghuis DO, Boersma CJ, van Zoelen EJ, Geurts van Kessel A, Olijve W (novembar 1995). "Fine mapping of the human bone morphogenetic protein-4 gene (BMP4) to chromosome 14q22-q23 by in situ hybridization". Genomics. 27 (3): 559–60. doi:10.1006/geno.1995.1096. hdl:2066/22049. PMID 7558046.

[pmid7579580-5] Oida S, Iimura T, Maruoka Y, Takeda K, Sasaki S (novembar 1995). "Cloning and sequence of bone morphogenetic protein 4 (BMP-4) from a human placental cDNA library". DNA Seq. 5 (5): 273–5. doi:10.3109/10425179509030980. PMID 7579580.

[pmid7763240-6] Aono A, Hazama M, Notoya K, Taketomi S, Yamasaki H, Tsukuda R, Sasaki S, Fujisawa Y (maj 1995). "Potent ectopic bone-inducing activity of bone morphogenetic protein-4/7 heterodimer". Biochem. Biophys. Res. Commun. 210 (3): 670–7. doi:10.1006/bbrc.1995.1712. PMID 7763240.

[pmid10559902-7] Botchkarev VA, Botchkareva NV, Roth W, Nakamura M, Chen LH, Herzog W, Lindner G, McMahon JA, Peters C, Lauster R, McMahon AP, Paus R (juli 1999). "Noggin is a mesenchymally derived stimulator of hair-follicle induction". Nat. Cell Biol. 1 (3): 158–64. doi:10.1038/11078. PMID 10559902. S2CID 8777441.

[pmid11677055-8] Knöchel S, Dillinger K, Köster M, Knöchel W (novembar 2001). "Structure and expression of Xenopus tropicalis BMP-2 and BMP-4 genes". Mech. Dev. 109 (1): 79–82. doi:10.1016/S0925-4773(01)00506-8. PMID 11677055. S2CID 792305.

[9] Graham et al., 1994

[10] Mira H, Andreu Z, Suh H, Lie DC, Jessberger S, Consiglio A, San Emeterio J, Hortigüela R, Marqués-Torrejón MA, Nakashima K, Colak D, Götz M, Fariñas I, Gage FH (2010). "Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult hippocampus". Cell Stem Cell. 7 (1): 78–89. doi:10.1016/j.stem.2010.04.016. PMID 20621052.

[11] Colak D, Mori T, Brill MS, Pfeifer A, Falk S, Deng C, Monteiro R, Mummery C, Sommer L, Götz M (2008). "Adult neurogenesis requires Smad4-mediated bone morphogenic protein signaling in stem cells". The Journal of Neuroscience. 28 (2): 434–446. doi:10.1523/JNEUROSCI.4374-07.2008. PMC 6670509. PMID 18184786.

[pmid24744701-12] Farioli-Vecchioli S, Ceccarelli M, Saraulli D, Micheli L, Cannas S, D'Alessandro F, Scardigli R, Leonardi L, Cinà I, Costanzi M, Mattera A, Cestari V, Tirone F (2014). "Tis21 is required for adult neurogenesis in the subventricular zone and for olfactory behavior regulating cyclins, BMP4, Hes1/5 and Ids". Front Cell Neurosci. 8: 98. doi:10.3389/fncel.2014.00098. PMC 3977348. PMID 24744701.

[pmid12801979-13] Nilsson EE, Skinner MK (oktobar 2003). "Bone morphogenetic protein-4 acts as an ovarian follicle survival factor and promotes primordial follicle development". Biol. Reprod. 69 (4): 1265–72. doi:10.1095/biolreprod.103.018671. PMID 12801979. S2CID 2141586.

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