Role of SRF in early cardiac Morphogenesis

SRF 在早期心脏形态发生中的作用

• 批准号: 7100178
• 负责人: ROBERT A. SCHWARTZ
• 金额: $ 36.08万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7100178
• 关键词: congenital heart disorder; developmental genetics; heart; histogenesis; 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发现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定型中起主导作用。最近同源重组敲除小鼠SRF基因位点支持了这样的观察，即在小鼠胚胎发生过程中，SRF是心脏中胚层出现所必需的。然而，由于SRF无效突变体导致如此早期的胚胎致死性，我们不知道SRF实际上如何促进早期心肌定型和分化。我们有强有力的证据表明，SRF作为一个生肌限制性平台与其他调控蛋白相互作用，并最终改变特定基因程序的调控。我们的研究表明SRF促进小鼠同源框转录因子Nkx 2 -5和GATA 4与血清反应元件的结合，导致内源性α-心脏肌动蛋白基因的激活，提供了令人信服的证据，即SRF、Nkx 2 -5和加塔-4与内源性α-心脏肌动蛋白基因相互作用;提供了令人信服的证据表明，SRF，Nkx 2 -5和GAT-4是相互作用的，并有助于心脏基因表达。在拟议的研究中，我们将确定SRF基因是如何在心脏基因表达的外观调节。在本研究中，我们将探讨SRF基因在小鼠胚胎心脏发育过程中的调控机制。该提案的具体目的是：目的I：编码SRF基因的小鼠基因组位点如何允许心脏发生期间的高水平表达？假设1：生长因子如BMP 2/4和FGF 4信号激活心脏新月体中SRF基因的表达。这些生长因子形态发生素诱导的心野表达的重叠转录因子Nkx 2 -5、Smads、加塔-4和-5和TBX 2、3和5参与激活和/或抑制SRF的表达，SRF_5作为另一种切割的SRF，作为阻断心脏发生的显性负性因子。这些转录因子激活心脏特异性表达SRF在指定早期心脏中胚层有直接的作用？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转化为主动脉弓祖细胞中起作用目的III：SRF是否需要与Nkx 2 -5和GATA 4直接相关以激活心源性程序？假设三：MADS盒作为一个主调控平台，允许根据与MADS盒α I和/或α II螺旋的特定因子-因子关联来切换遗传程序。SRF与Nkx 2 -5和GATA 4之间共享的组合相互作用对于中胚层前体细胞向定向心脏中胚层的进展是必需的，并且需要通过MADS盒的α I螺旋的特异性物理关联。