Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development
Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development
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DOI：
10.1242/dev.123539
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发表时间：
2015-08-15
期刊：
影响因子：
4.6
通讯作者：
McNeill, Helen
中科院分区：
文献类型：
--
作者：
Badouel, Caroline;Zander, Mark A.;McNeill, Helen
哺乳动物大脑发育需要神经前体增殖、分化和细胞组织之间的协调，以创建成人大脑的复杂神经元网络。在这里，我们研究了非典型钙粘蛋白Fat1和Fat4在这个过程中的作用。我们发现，在小鼠胚胎中的脂肪1突变导致颅神经管关闭缺陷，伴随着皮质前体细胞增殖的增加和改变顶端连接，与顶端收缩和肌动蛋白积累的扰动。类似地，通过子宫内电穿孔敲低皮质前体中的Fat1导致放射状神经胶质前体的过度增殖。Fat1与相关的钙粘蛋白Fat4在遗传上相互作用以调节这些过程。蛋白质组学分析表明，脂肪1和脂肪4绑定不同的肌动蛋白调节和连接蛋白。体外数据表明，脂肪1和脂肪4形成顺式异二聚体，提供了一种机制，使他们的不同的相互作用。我们提出了一个模型，其中Fat1和Fat4结合协调不同的途径在顶端连接调节神经祖细胞增殖，神经管关闭和顶端收缩。
Mammalian brain development requires coordination between neural precursor proliferation, differentiation and cellular organization to create the intricate neuronal networks of the adult brain. Here, we examined the role of the atypical cadherins Fat1 and Fat4 in this process. We show that mutation of Fat1 in mouse embryos causes defects in cranial neural tube closure, accompanied by an increase in the proliferation of cortical precursors and altered apical junctions, with perturbations in apical constriction and actin accumulation. Similarly, knockdown of Fat1 in cortical precursors by in utero electroporation leads to overproliferation of radial glial precursors. Fat1 interacts genetically with the related cadherin Fat4 to regulate these processes. Proteomic analysis reveals that Fat1 and Fat4 bind different sets of actin-regulating and junctional proteins. In vitro data suggest that Fat1 and Fat4 form cis-heterodimers, providing a mechanism for bringing together their diverse interactors. We propose a model in which Fat1 and Fat4 binding coordinates distinct pathways at apical junctions to regulate neural progenitor proliferation, neural tube closure and apical constriction.