The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors
The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors
复制标题
DOI：
10.1073/pnas.0707456104
复制
发表时间：
2007-09-25
影响因子：
11.1
通讯作者：
Zoghbi, Huda Y.
中科院分区：
文献类型：
--
作者：
Flora, Adriano;Garcia, Jesus J.;Zoghbi, Huda Y.
前神经因子代表了指定哺乳动物神经系统中所有不同神经元所需的< 10个转录调节因子。如此少的因素造成这种多样性的机制尚不清楚。我们认为蛋白质与前膜因子相互作用赋予了这种特异性。为了验证这一假设，我们分离了与Math1相互作用的蛋白质，Math1是神经祖细胞群（菱形唇）的建立所必需的前神经转录因子，产生了多个后脑结构，并鉴定了e蛋白Tcf4。有趣的是，TCF4的单倍体充足性导致了皮特-霍普金斯精神发育迟缓综合征，强调了该蛋白在神经发育中的重要作用。为了研究Math1/ Tcf4相互作用在体内的功能相关性，我们研究了Tcf4（-/-）小鼠，发现它们破坏了脑桥核的发育。令人惊讶的是，尽管Math1和Tcf4在整个菱形唇上表达，但这种选择性缺陷并不影响其他菱形唇源核。重要的是，任何其他e蛋白编码基因的缺失都不会对依赖math1的神经元产生可检测到的影响，这表明Tcf4在不同的神经祖细胞中具有特殊作用。我们的研究结果首次在体内证明了在原基螺旋-环-螺旋因子和特定e蛋白之间形成的二聚体的排他功能，为调控哺乳动物神经系统发育的转录程序的潜在机制提供了见解。
Proneural factors represent < 10 transcriptional regulators required for specifying all of the different neurons of the mammalian nervous system. The mechanisms by which such a small number of factors creates this diversity are still unknown. We propose that proteins interacting with proneural factors confer such specificity. To test this hypothesis we isolated proteins that interact with Math1, a proneural transcription factor essential for the establishment of a neural progenitor population (rhombic lip) that gives rise to multiple hindbrain structures and identified the E-protein Tcf4. Interestingly, haploin-sufficiency of TCF4 causes the Pitt-Hopkins mental retardation syndrome, underscoring the important role for this protein in neural development. To investigate the functional relevance of the Math1/ Tcf4 interaction in vivo, we studied Tcf4(-/-) mice and found that they have disrupted pontine nucleus development. Surprisingly, this selective deficit occurs without affecting other rhornbic lip-derived nuclei, despite expression of Math1 and Tcf4 throughout the rhombic lip. Importantly, deletion of any of the other E-protein-encoding genes does not have detectable effects on Math1-dependent neurons, suggesting a specialized role for Tcf4 in distinct neural progenitors. Our findings provide the first in vivo evidence for an exclusive function of dimers formed between a proneural basic helix-loop-helix factor and a specific E-protein, offering insight about the mechanisms underlying transcriptional programs that regulate development of the mammalian nervous system.