Regulation of cortical progenitors by Sufu and Shh signaling

Sufu 和 Shh 信号传导对皮质祖细胞的调节

• 批准号: 9119859
• 负责人: SAMUEL JEREMY PLEASURE
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119859
• 关键词: Acceleration; Age; Autistic Disorder; Cells; Cerebral cortex; Characteristics; Data; Defect; Development; Dorsal; Embryo; Etiology; Failure; Family; Forebrain Development; Funding; Grant; Health; In Vitro; Knowledge; LoxP-flanked allele; Mediating; Molecular; Mus; Neuroglia; Neurons; Pattern; Phenotype; Process; Production; Prosencephalon; Regulation; Repression; Role; SHH gene; Schizophrenia; Signal Pathway; Staging; Stem cells; Stereotyping; System; Techniques; Testing; Ventricular; adult neurogenesis; base; brain repair; dentate gyrus; discount; genetic resource; gliogenesis; in vivo; inhibitor/antagonist; insight; mutant; neocortical; nerve stem cell; nervous system disorder; neurogenesis; neuron development; neuropsychiatric disorder; novel; novel strategies; oligodendrocyte precursor; postnatal; precursor cell; progenitor; relating to nervous system; smoothened signaling pathway; transcription factor

 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.

 描述（由申请人提供）：在初步研究中，我们发现 E10.5 后皮质中缺乏 Sufu 的小鼠几乎完全无法生成浅层皮质投射神经元，但能更完整地生成深层皮质神经元。对这些突变体的初步分析表明，皮质发生过程中出现的浅表神经元祖细胞逐渐失去其适当的表型，取而代之的是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）删除 Sufu 对浅表神经元的产生基本上没有影响，表明 Sufu 在控制神经元的祖细胞多样化和细胞命运方面具有暂时的显着作用。有趣的是，当我们检查 E13.5 时 Sufu 缺失的小鼠时，发现皮质中胚胎晚期和出生后早期少突胶质细胞前体细胞的产生明显加速。 这些初步结果使我们提出了一个新的主要假设，即早期皮质心室区（E10.5 和 E13.5 之间）Shh 信号传导的受控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 信号传导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深远影响。以下目标将测试这些假设并检查控制这些表型的细胞和分子机制。 目标 1：确定 Shh 信号传导如何阻止浅层皮层神经元的产生。 目标 2：确定 Shh 信号在控制出生后神经发生和皮质中少突胶质细胞前体生成中的作用。 这里提出的研究将为两个重要问题提供重要的新见解 - 1）Shh 信号在前脑发育中的作用是什么；2）深层神经元、浅层神经元和神经胶质细胞的产生是如何有序进行的。这对于该领域非常重要，对于理解神经精神疾病的发育基础也具有重要意义。