Role of SRF in early cardiac Morphogenesis

SRF 在早期心脏形态发生中的作用

• 批准号: 6930514
• 负责人: ROBERT A. SCHWARTZ
• 金额: $ 35.03万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6930514
• 关键词: cardiogenesis; congenital heart disorder; developmental genetics; heart; laboratory mouse; mammalian embryology; transcription factor

Specification of the cardiac lineage and expression of cardiac specified genes may require combinatorial interactions between transcription found to enriched during the emergence of cardiac progenitor cells. Serum response factor (SRF) may play a leading role in the commitment of cardiac progenitors The recent homologous recombinant knockout of the murine SRF gene locus supports the observation that SRF is required for the appearance of cardiac mesoderm during mouse embryogenesis. However, because SRF null mutants cause such an early embryonic lethality we do not know how SRF actually contributes to early heart muscle commitment and differentiation. We have strong evidence that SRF acts as a myogenic restricted platform to interact with other regulatory proteins and ultimately alter the regulation of specific gene programs. Our studies suggest that SRF facilities binding of the murine homeobox transcription factor, Nkx2-5 and GATA4 to serum response elements resulting in the activation of the endogenous alpha-cardiac actin gene; provides compelling evidence that SRF, Nkx2-5 and GATA-4 are mutually interactive of the endogenous alpha-cardiac actin gene; provides compelling evidence that SRF, Nkx2-5 and GAT-4 are mutually interactive and instrumental for cardiac gene expression. In the proposed studies, we will determine how the SRF gene is regulated during the appearance of cardiac gene expression. In the proposed studies, we will determine how the SRF gene is regulated during the appearance of cardiac mesoderm and the elaboration and formation of the embryonic mouse heart. The Specific Aims of the proposal are: Aim I: How does the murine genomic loci encoding the SRF gene allow for the high level expression during cardiogenesis? Hypothesis 1: Growth factors such as BMP2/4 and FGF4 signals activate SRF gene expression in the cardiac crescent. Overlapping transcription factors Nkx2-5, Smads, GATA-4 and -5, and TBX2,3 and 5 expressed in the cardiac field, induced by these growth factor morphogens, are involved with activating and or repressing SRF expression, SRF_5 an alternative sliced SRF acts as a dominant negative factor that blocks cardiogenesis. These transcription factors activate cardiac specific expression SRF have a direct role in specifying early cardiac mesoderm? Hypothesis 2: The conversion of mesoderm to cardiogenic lineages to drive the cardiac program in the intact mouse embryo requires SRF gene activity. SRF has a role in L/R asymmetry and the conversion of neural crest cells into aortic arch progenitors Aim III: Does SRF require direct association with Nkx2-5 and GATA4 to activate the cardiogenic program? Hypothesis 3: The MADS Box serves as a master regulatory platform that allows for switching of genetic programs depending upon specific factor-factor associations with either of its MADS Box alphaI and or alphaII coils. Combinatorial interactions shared between SRF with Nkx2-5 and GATA4 is obligatory for the progression of mesoderm precursor cells to committed cardiac mesoderm and requires specific physical association through the alphaI coil of the MADS box.

心脏谱系的指定和心脏特定基因的表达可能需要在心脏祖细胞出现期间富集的转录之间的组合相互作用。血清反应因子（SRF）可能在心脏祖细胞的承诺中起主导作用，最近对小鼠SRF基因位点的同源重组敲除支持了SRF在小鼠胚胎发生过程中心脏中胚层的出现所必需的观察。然而，由于SRF无效突变导致如此早期的胚胎死亡，我们不知道SRF实际上如何促进早期心肌的承诺和分化。我们有强有力的证据表明SRF作为一个肌源性受限平台与其他调节蛋白相互作用，并最终改变特定基因程序的调节。我们的研究表明，SRF可将小鼠同源盒转录因子Nkx2-5和GATA4与血清反应元件结合，从而激活内源性α -心脏肌动蛋白基因；提供了令人信服的证据，表明SRF， Nkx2-5和GATA-4是内源性α -心脏肌动蛋白基因的相互作用；提供了令人信服的证据，表明SRF， Nkx2-5和GAT-4是相互作用的，有助于心脏基因表达。在拟议的研究中，我们将确定SRF基因在心脏基因表达过程中是如何被调控的。在拟议的研究中，我们将确定SRF基因在心脏中胚层的出现和胚胎小鼠心脏的发育和形成过程中是如何被调控的。该提案的具体目的是：目的1:SRF基因编码的小鼠基因组位点如何在心脏发生过程中允许高水平表达？假设1：生长因子如BMP2/4和FGF4信号激活心脏月牙中SRF基因表达。重叠转录因子Nkx2-5， Smads， GATA-4和-5，TBX2,3和5在这些生长因子形态因子诱导下，在心脏区表达，参与激活或抑制SRF表达，SRF_5作为一种替代切片SRF作为一个主要的负面因子，阻断心脏发生。这些转录因子激活心脏特异性表达SRF在确定早期心脏中胚层有直接作用。假设2：在完整的小鼠胚胎中，中胚层向心源性谱系的转化，以驱动心脏程序需要SRF基因活性。SRF在L/R不对称和神经嵴细胞向主动脉弓祖细胞的转化中起作用Aim III: SRF是否需要与Nkx2-5和GATA4直接关联才能激活心源性程序？假设3:MADS Box作为一个主要的调控平台，允许基因程序的切换，这取决于特定的因子-因子与它的MADS Box α和或α ii线圈中的任何一个的关联。SRF与Nkx2-5和GATA4之间的组合相互作用对于中胚层前体细胞向心脏中胚层的进展是必需的，并且需要通过MADS盒的alpha线圈进行特定的物理关联。