胚胎發(fā)育的細(xì)胞增殖和分化

胚胎發(fā)育的細(xì)胞增殖和分化基礎(chǔ)醫(yī)學(xué)院組織胚胎學(xué)系肖玲概述概述胚胎發(fā)育過程：細(xì)胞生長分化識別遷移死亡功能表達(dá)組織和器官的形成等

細(xì)胞增殖：細(xì)胞數(shù)量的增加

細(xì)胞分裂

細(xì)胞分化：不同類型細(xì)胞的形成

形態(tài)結(jié)構(gòu)和生理功能發(fā)生專一性的改變6ProliferationofeukaryoticcellCellgrowthDNAreplicationCelldivisionWhatiscellcycle?細(xì)胞周期,---從上一次有絲分裂結(jié)束到下一次有絲分裂完成所經(jīng)歷的整個(gè)過程。一、細(xì)胞增殖7PhasesofthecellcycleG1phaseSphaseG2phaseMphase8Phaseofcellcycle

M-PhaseMitosisCytokinesisInterphaseG1=GapbetweenMandSS=Synthesis(DNAandcentrosomesreplicated)G2=GapbetweenSandM9CellCycleRegulation

Cyclins

CyclinDependentKinases(CDKs)

CyclinDependentKinasesInhibitors(CDKIS)勒蘭德·哈特韋爾發(fā)現(xiàn)了大量控制細(xì)胞周期的基因，其中一種被稱為“START”的基因?qū)刂聘鱾€(gè)細(xì)胞周期的最初階段具有決定性的作用。保羅·納斯的貢獻(xiàn)是，在哈特韋爾的基礎(chǔ)上，通過基因與分子法發(fā)現(xiàn)了調(diào)節(jié)細(xì)胞周期的一種關(guān)鍵物質(zhì)CDK（細(xì)胞周期蛋白依賴激酶），CDK是通過對其他蛋白質(zhì)的化學(xué)作用來驅(qū)動(dòng)細(xì)胞周期的。蒂莫西·亨特的貢獻(xiàn)是首次發(fā)現(xiàn)了調(diào)節(jié)CDK功能的物質(zhì)CYCLIN（細(xì)胞周期蛋白）。11TheNobelPrizeinPhysiologyorMedicine2001wasawardedjointlytoLelandH.Hartwell,TimHuntandSirPaulM.Nurse"fortheirdiscoveriesofkeyregulatorsofthecellcycle".LelandH.HartwellTimHuntSirPaulM.Nurse①連續(xù)分裂細(xì)胞，在細(xì)胞周期中連續(xù)運(yùn)轉(zhuǎn)因而又稱為周期細(xì)胞，如表皮生發(fā)層細(xì)胞、部分骨髓細(xì)胞。

②休眠細(xì)胞暫不分裂，但在適當(dāng)?shù)拇碳は驴芍匦逻M(jìn)入細(xì)胞周期，稱G0期細(xì)胞，如淋巴細(xì)胞、肝、腎細(xì)胞等。

③不分裂細(xì)胞，指不可逆地脫離細(xì)胞周期，不再分裂的細(xì)胞，又稱終端細(xì)胞，如神經(jīng)、肌肉、多形核細(xì)胞等等。成體細(xì)胞分裂胚胎時(shí)期細(xì)胞分裂早期：卵裂1.細(xì)胞在兩次分裂之間沒有生長期，細(xì)胞體積并不增大，基因在早期不表達(dá)。2.致密化：細(xì)胞核和細(xì)胞質(zhì)的比值迅速增加，細(xì)胞之間的粘附加強(qiáng)。3.細(xì)胞周期是連續(xù)的S期和M期的交替。胚胎時(shí)期細(xì)胞分裂早期：卵裂桑葚胚:致密化極性17Stagesofmouseandhumanpreimplantationdevelopment.(TE:trophectoderm;ICM:innercellmass;EPI:epiblast;PE:primitiveendoderm)1819CockburnK,RossantJ.Makingtheblastocyst:lessonsfromthemouse.JClinInvest.2010,120(4):995-1003.20異常卵裂卵裂時(shí)間延遲:植入失敗不規(guī)則卵裂:胚胎異常發(fā)育多精受精:多倍體，最終死亡或畸形單卵雙胎或多胎:兩個(gè)胚泡，單獨(dú)的羊膜和絨毛膜；兩個(gè)內(nèi)細(xì)胞群，單獨(dú)的羊膜，共有絨毛膜和胎盤；兩個(gè)原條，共有羊膜和絨毛膜2122Siamesetwins23早期胚胎發(fā)育的調(diào)控Beforegenomeactivation母源作用基因(miRNAs,transcriptionalfactors,DNAmethyltransferase,…)Aftergenomeactivation

Transcriptionalfactors(Cdx2,Oct4…)HeatshockproteinsCytokines…2425Cdx2Oct4Oct-4:許多基因的轉(zhuǎn)錄因子特異性表達(dá)于全能細(xì)胞中26當(dāng)一個(gè)細(xì)胞分裂有絲分裂產(chǎn)生兩個(gè)“染色體完全相同的子細(xì)胞”。SO,HOWDOTHESECELLSBECOMEDIFFERENTFROMONEANOTHER?27二、細(xì)胞分化細(xì)胞分化是指合子發(fā)育成為個(gè)體的過程中細(xì)胞之間逐漸產(chǎn)生穩(wěn)定差異的過程。發(fā)育生物學(xué)研究之核心。28在細(xì)胞分化的基礎(chǔ)上，胚胎逐漸產(chǎn)生出許多不同的組織、器官和系統(tǒng)，協(xié)調(diào)地組成一個(gè)復(fù)雜、精巧、能自主生活的生命個(gè)體。29在細(xì)胞之間出現(xiàn)可識別的形態(tài)和功能差異之前，細(xì)胞已經(jīng)具備向特定方向分化，最終形成具有一定表型特征細(xì)胞的能力，這種細(xì)胞的發(fā)育選擇稱為細(xì)胞決定。決定先于分化。細(xì)胞決定的主要標(biāo)志是細(xì)胞內(nèi)部開始合成特異性的蛋白質(zhì)。細(xì)胞決定與細(xì)胞分化30CytoplasmicDeterminantsandInductiveSignalsAnegg’scytoplasmcontainsRNA,proteins,andothersubstancesthataredistributedunevenlyintheunfertilizedegg.Cytoplasmicdeterminantsarematernalsubstancesintheeggthatinfluenceearlydevelopment.Asthezygotedividesbymitosis,cellscontaindifferentcytoplasmicdeterminants,whichleadtodifferentgeneexpression.31(a)CytoplasmicdeterminantsintheeggTwodifferentcytoplasmicdeterminantsUnfertilizedeggcellSpermNucleus32(a)CytoplasmicdeterminantsintheeggTwodifferentcytoplasmicdeterminantsUnfertilizedeggcellSpermFertilizationZygoteNucleus33(a)CytoplasmicdeterminantsintheeggTwodifferentcytoplasmicdeterminantsUnfertilizedeggcellSpermFertilizationZygoteMitoticcelldivisionTwo-celledembryoNucleus34(b)InductionbynearbycellsSignalmolecule(inducer)SignaltransductionpathwayEarlyembryo(32cells)NUCLEUSSignalreceptor35TotipotentPluripotentUnipotentDifferentiatedTotipotentPluripotentUnipotentDifferentiatedTotipotent→Pluripotent→Unipotent→Differentiated36細(xì)胞分化的影響因素基因的調(diào)控細(xì)胞之間的作用激素環(huán)境因素受精卵發(fā)育形成的細(xì)胞含有相同基因但在發(fā)育中只有5-10%基因表達(dá)(人類基因總數(shù)約3萬--5萬)且表達(dá)的基因差異較大Why?基因的調(diào)控38基因的調(diào)控管家基因(house-keepinggenes)：是指所有細(xì)胞中均要表達(dá)的一類基因，其產(chǎn)物是對維持細(xì)胞基本生命活動(dòng)所必需的。如微管蛋白基因、糖酵解酶系基因與核糖體蛋白基因等。(Helper)奢侈基因(Luxurygene)：即組織特異性基因（tissue-specificgenes），是指不同類型細(xì)胞中特異性表達(dá)的基因，指導(dǎo)產(chǎn)生細(xì)胞分化時(shí)出現(xiàn)的各種特異蛋白。(Determinant)3940ExampleMyoblasts

producemuscle-specificproteinsandformskeletalmusclecellsMyoDisoneofseveral“masterregulatorygenes”thatproduceproteinsthatcommitthecelltobecomingskeletalmuscleTheMyoDproteinisatranscriptionfactorthatbindstoenhancersofvarioustargetgenes41EmbryonicprecursorcellNucleusOFFDNAMasterregulatorygenemyoDOthermuscle-specificgenesOFF42EmbryonicprecursorcellNucleusOFFDNAMasterregulatorygenemyoDOthermuscle-specificgenesOFFOFFmRNAMyoDprotein(transcriptionfactor)Myoblast(determined)43EmbryonicprecursorcellNucleusOFFDNAMasterregulatorygenemyoDOthermuscle-specificgenesOFFOFFmRNAMyoDprotein(transcriptionfactor)Myoblast(determined)mRNAmRNAPartofamusclefiber(fullydifferentiatedcell)MyoD44EmbryonicprecursorcellNucleusOFFDNAMasterregulatorygenemyoDOthermuscle-specificgenesOFFOFFmRNAMyoDprotein(transcriptionfactor)Myoblast(determined)mRNAmRNAmRNAmRNAMyosin,othermuscleproteins,andcellcycle–blockingproteinsPartofamusclefiber(fullydifferentiatedcell)MyoDAnothertranscriptionfactor46細(xì)胞之間的作用細(xì)胞誘導(dǎo)細(xì)胞抑制微環(huán)境：細(xì)胞外基質(zhì)47細(xì)胞誘導(dǎo)Inductionistheprocessbywhichonegroupofcellsproducesasignalthatdeterminesthefateofasecondgroupofcells.4849細(xì)胞外基質(zhì)

Extracellularmatrix(ECM)ECMcancontrolthedifferentiationbyinfluencingtheintracellulargeneexpressionsviasignaltransduction.ExogenousECMpreventstheinhibitionofskeletalmuscledifferentiationbyproteoglycansynthesisinhibitors.OssesN,andBrandanEAmJPhysiolCellPhysiol2002;282:C383-C394ChlorateandBDXcaninhibittheproteoglycansynthesis.51激素SteroidsPeptidesToinfluencethegeneexpressionsthroughbindingwiththecorrespondingreceptorsTargetcells52環(huán)境因素1)生物因素病毒:風(fēng)疹病毒→白內(nèi)障，耳聾，心臟缺陷;巨細(xì)胞病毒→失明，小頭畸形，肝脾腫大；單純皰疹病毒→小頭，

小眼53

2)物理輻射，機(jī)械壓力，創(chuàng)傷輻射：第二次世界大戰(zhàn)：原子彈在日本爆炸。幸存的孕婦：28%中止；25%孩子死亡＜1年；25%中樞神經(jīng)系統(tǒng)畸形。543)化學(xué)化工：亞硝酸鹽，汞，鉛，等藥物：沙利度胺（阿米莉亞和殘肢）

554)其它缺氧營養(yǎng)不足............56Susceptibleperiod

1)Dependentonthedevelopmentalstage.Theembryonicperiod(3-8weeks)isthehighestsusceptibleperiod.

572)Differentorganshavedifferentsusceptibleperiodcorresp