Heterogeneity of forebrain neural precursors

发育神经生物学的两个主要目标是鉴定形成中枢神经系统的生发细胞，并描述这些细胞产生适当数量和类型的神经元和神经胶质细胞的细胞和分子机制。最近，对小鼠的逆转录病毒和遗传学研究表明，放射状胶质细胞（RGCs）通过产生有丝分裂后神经元，然后作为这些子细胞向新皮质壁迁移的基质，对新皮质的发育起着重要作用。此外，RGCs现在被认为是新皮层的产前干细胞，一些研究小组提出，在胚胎神经发生过程中，新皮层心室区（VZ）仅由RGCs组成。然而，目前尚不清楚单一的VZ前体细胞类型如何产生大量多样性的新皮层神经元。此外，由于在人类和猴子的VZ中发现了多种类型的前体，灵长类动物VZ的这种异质性是否代表了啮齿动物和灵长类动物的进化分歧也是一个问题。我们已经在体内小鼠VZ中发现了显著的前体多样性。通过使用多种组织学、遗传学和超微结构技术——其中许多是我们在这个项目中创新的——我们现在表明，RGCs与另一种类型的VZ细胞相连，我们将其命名为短神经前体细胞（SNP）。我们证明RGCs和SNPs可以在形态学，分子和增殖动力学和谱系电位方面进行区分。此外，我们还发现了不同类型的RGCs之间的体内差异，这表明并非所有的RGCs都是多能干细胞。总之，我们发表的和初步的数据从根本上改变了我们对哺乳动物VZ组成的理解，并清楚地表明，这种生发室的多样性是正常的新皮质生长和功能所必需的。该项目将全面测试VZ在胚胎发育过程中通过共同VZ祖先的多样化而成为异质的整体假设，并且这种复杂性对于正常的新皮层生长是必要的。

DESCRIPTION (provided by applicant): Two major goals of developmental neurobiology are to identify the germinal cells which form the central nervous system and to characterize the cellular and molecular mechanisms by which these cells generate the proper numbers and types of neurons and glial cells. Recently, retroviral and genetic studies in mice have demonstrated that radial glial cells (RGCs) contribute significantly to neocortical development by generating postmitotic neurons and then serving as the substrate for the migration of those daughter cells into the neocortical wall. Furthermore, RGCs are thought now to be the prenatal stem cell of the neocortex, and several groups have suggested that the neocortical ventricular zone (VZ) is composed solely of RGCs during embryonic neurogenesis. However, it remains unclear how a single VZ precursor cell type can generate the vast diversity of neocortical neurons. In addition, since multiple types of precursors have been found in the human and monkey VZ, whether this heterogeneity in the primate VZ represents evolutionary divergence of rodents and primates also remains a question. We have uncovered significant precursor diversity in the in vivo murine VZ. Through the use of multiple histological, genetic and ultrastructural techniques - many of which we innovated for this project - we now show that RGCs are joined by another type of resident VZ cell which we have named the short neural precursor cell (SNP). We demonstrate that RGCs and SNPs can be distinguished morphologically, molecularly, and with respect to proliferation kinetics and lineage potential. In addition, we have uncovered in vivo differences between classes of RGCs which suggest that not all RGCs are multipotent stem cells. Taken together, our published and Preliminary Data fundamentally alter our understanding of the composition of the mammalian VZ and clearly indicate that diversity in this germinal compartment is required for proper neocortical growth and function. This project will comprehensively test the overall hypothesis that the VZ becomes heterogeneous during embryonic development through diversification of a common VZ ancestor and that this complexity is necessary for proper neocortical growth.