Role of NeuroD family genes in the control of neocortical layering

神经元回路的正确组装对成人大脑的功能至关重要。大脑皮层是哺乳动物进化的顶峰，可能是最复杂的器官之一。Neurod家族的神经性bHLH转录因子(Neurod1、Neurod2和Neurod6)在背侧端脑的年轻神经元中表达，长期以来一直被认为在神经元的决定和分化中发挥重要作用。然而，到目前为止，它们在哺乳动物大脑皮层发育中的作用还没有被研究过。BHLH域的高序列相似性和发育中的新皮质中高度重叠的表达模式表明功能冗余。为了克服后者，我们产生了三个基因都被删除的复合突变小鼠。我们的初步工作在神经三重突变中发现了几个有趣的表型。在新皮质中缺乏Neurod1、Neurod2和Neurod6的动物表现出强烈的神经元分化和大脑皮层细胞结构缺陷。为了了解这些现象，我们提出了Neurod1/2/6三重突变体的全谱特征。这包括形态特征、神经元迁移分析、细胞命运决定以及细胞存活和神经前体细胞增殖的研究。我们还旨在确定在发育中的大脑皮层中控制这些过程的Neurod基因下游的分子机制。我们提出的对大脑皮层神经缺陷神经元的研究旨在为大脑皮层发育的分子基础提供有价值的见解。

Correct assembly of neuronal circuits is vital for the function of the adult brain. Cerebral cortex is the crown of mammalian evolution and is probably one of the most complex organs. Neuronal bHLH transcription factors of the NeuroD family (Neurod1, Neurod2, and Neurod6) are expressed in young neurons of the dorsal telencephalon and have long been speculated to play an important role in neuronal determination and differentiation. However, their function in the development of the mammalian cerebral cortex has not been investigated so far. High sequence similarity in the bHLH domain and highly overlapping expression patterns in the developing neocortex suggested function redundancy. In order to overcome the latter, we generated compound mutant mice where all three genes were deleted.Our preliminary work has uncovered several interesting phenotypes in NeuroD triple mutants. Animals deficient for NeuroD1, Neurod2, and Neurod6 in the neocortex show strong deficits of neuronal differentiation and cerebral cortex cytoarchitechture.To understand these phenomena we propose a full spectrum characterization of Neurod1/2/6 triple mutants. This involves morphological characterization, neuronal migration analysis, investigation of cell fate determination as well as cell survival and neuronal progenitors proliferation. We also aim to identify molecular mechanisms downstream of Neurod genes that control these processes in the developing cerebral cortex. Our proposed study of NeuroD–deficient neurons in the cerebral cortex aims to provide valuable insights into the molecular basis of cerebral cortex development.