Flora Adriano, Garcia Jesus J, Thaller Christina, Zoghbi Huda Y
Howard Hughes Medical Institute, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15382-7. doi: 10.1073/pnas.0707456104. Epub 2007 Sep 18.
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, haploinsufficiency 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 rhombic 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.
原神经因子代表了不到10种转录调节因子，它们是确定哺乳动物神经系统中所有不同神经元所必需的。如此少量的因子创造这种多样性的机制仍然未知。我们提出，与原神经因子相互作用的蛋白质赋予了这种特异性。为了验证这一假设，我们分离了与Math1相互作用的蛋白质，Math1是一种原神经转录因子，对建立产生多种后脑结构的神经祖细胞群（菱唇）至关重要，并鉴定出E蛋白Tcf4。有趣的是，TCF4单倍体不足会导致皮特-霍普金斯智力发育迟缓综合征，这突出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基因敲除小鼠，发现它们的脑桥核发育受到破坏。令人惊讶的是，尽管Math1和Tcf4在整个菱唇中都有表达，但这种选择性缺陷在不影响其他菱唇衍生核的情况下发生。重要的是，删除任何其他编码E蛋白的基因对依赖Math1的神经元没有可检测到的影响，这表明Tcf4在不同的神经祖细胞中具有特殊作用。我们的发现首次提供了体内证据，证明原神经碱性螺旋-环-螺旋因子与特定E蛋白之间形成的二聚体具有独特功能，这为调节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。
