Determining the role of Sufu in adult neurogenesis

 描述(申请人提供)：在初步研究中，我们发现E10.5后大脑皮质缺乏Sufu的小鼠几乎完全不能产生浅层皮质投射神经元，但更完整地产生深层皮质神经元。对这些突变体的初步分析表明，在皮质发生过程中出现的浅层神经元的祖细胞逐渐失去了适当的表型，取而代之的是具有腹侧前脑祖细胞和少突胶质细胞前体的特征。值得注意的是，在稍晚的年龄(E13.5)，Sufu的缺失对浅层神经元的产生基本上没有影响，这表明Sufu在控制神经元的祖细胞多样化和细胞命运方面发挥了时间上的尖锐作用。有趣的是，当我们检查E13.5缺失Sufu的小鼠时，在胚胎晚期和出生后早期，大脑皮质中少突胶质前体细胞的产生明显加速。这些初步结果导致我们提出了一个新的初步假设，即在早期皮质脑室区(E10.5至E13.5之间)对Shh信号的控制限制是新皮质神经元多样化所必需的，并允许从神经发生到寡发生的有序进展。此外，我们的第二个假设是，皮质中Shh信号的调节也对皮质发育过程中少突胶质细胞前体的产生产生了深远的影响。下面的目标将检验这些假说，并研究支配这些表型的细胞和分子机制。目的1：确定Shh信号如何阻断皮层浅层神经元的产生。目的2：确定Shh信号在控制出生后神经发生和皮质少突胶质前体细胞产生中的作用。本文提出的研究将为两个重要问题提供重要的新见解：1)Shh信号在发育中的前脑中起什么作用；2)深层神经元的产生是如何有序进行的，然后是浅层神经元，然后是神经胶质细胞。这对该领域非常重要，对理解神经精神疾病的发育基础也具有重要意义。

 DESCRIPTION (provided by applicant): In preliminary studies we found that mice lacking Sufu in the cortex after E10.5 have an almost complete failure to generate superficial cortical projection neurons but more intact production of deep layer cortical neurons. Preliminary analysis of these mutants demonstrates that progenitors for superficial neurons that appear during corticogenesis progressively lose their appropriate phenotype and instead take on the characteristics of ventral forebrain progenitors and oligodendrocyte precursors. Remarkably, deletion of Sufu at a slightly later age (E13.5) has essentially no effect on production of superficial neurons indicating a temporally sharp role for Sufu in controlling progenitor diversification and cell fate of neurons. Interestingly, when we examined mice with loss of Sufu at E13.5 there was a marked acceleration of the production of oligodendrocyte precursor cells at late embryonic and early postnatal stages in the cortex. These preliminary results have led us to propose a novel primary hypothesis, that controlled restriction of Shh signaling in the early cortical ventricular zone (between E10.5 and E13.5) is required for diversification of neocortical neurons and allows orderly progression from neurogenesis to oligogenesis. Further, our secondary hypothesis is that regulation of Shh signaling in the cortex also has profound effects on the production of oligodendrocyte precursors during cortical development. The aims below will test these hypotheses and examine the cellular and molecular mechanisms governing these phenotypes. Aim 1: Determine how Shh signaling blocks production of superficial cortical neurons. Aim 2: Identify roles of Shh signaling in controlling the postnatal neurogenesis and the production of oligodendrocyte precursors in the cortex. The studies proposed here will provide major new insights into two important questions - 1) What is the role of Shh signaling in the developing forebrain and 2) How is the orderly progression of production of deep layer neurons, then superficial layer neurons then glial cells controlled. This is of great importance to the fiel and also of major relevance to understanding the developmental underpinning of neuropsychiatric disease.