REGIONAL DIFFERENTIATION DURING FOREBRAIN DEVELOPMENT

描述(改编自申请人的摘要)：目前不是 已知诱导--这发生在一个胚胎细胞群 影响另一种基因的表达和分化，发挥作用 在哺乳动物的主要区域和途径的发育中 前脑。对前脑感应的清楚理解是 至关重要，因为作为其基础的分子信号通路 这个过程可能会被环境毒素、基因突变、 减肥药、药品和滥用药物。这项提议将 评估额鼻之间诱导的假说 间充质，胚胎头部的表面上皮，以及 前脑神经上皮是形态发生和分化的基础 前脑的一个完整的功能区--嗅球-- 以及它的主要神经来源--嗅觉上皮。这个 研究人员将确定间充质之间的相互作用 而邻近的前脑或表面上皮细胞是必要的 模式化基因表达与神经元分化 推测为嗅觉上皮和前脑。的贡献 将对四个已建立的诱导信号分子进行评估。 维甲酸(RA)、声波刺猬(Shh)、成纤维细胞生长因子8 (FGF8)和骨形态发生蛋白4(BMP4)都是在离散的 前脑内或周围的细胞群、表面上皮和 间充质的我。调查员将分析推定的 嗅觉上皮或额鼻间充质提供独特的信号 启动嗅觉结构的形态发生和分化。 最后，他将评估归纳交互作用的程度 影响轴突投射的初始模式 嗅觉上皮和前脑。因此，这些实验将 确定区域性和非区域性诱导的细胞和分子基础 哺乳动物前脑中的通路发育。结果将会是 找出发育中的前脑的一个主要弱点 一系列环境毒素、药理制剂和遗传基因 疾病。前脑早期诱导的这种干扰 发展最终可能会损害独特的行为和 认知功能属于不同的前脑区域 和电路。

DESCRIPTION (Adapted from applicant's abstract): It is not currently known whether induction-which occurs when one embryonic cell group influences gene expression and differentiation in another, plays a role in the development of major regions and pathways in the mammalian forebrain. A clear understanding of induction in the forebrain is crucial since the molecular signaling pathways that underlie this process may be disrupted by environmental toxins, genetic mutations, dietary agents, pharmaceuticals, and drugs of abuse. This proposal will evaluate the hypothesis that induction between the frontonasal mesenchyme, the surface epithelium of the embryonic head, and the forebrain neuroepithelium underlies morphogenesis and differentiation of an entire functional subdivision of the forebrain-the olfactory bulb- as well as its major source of innervation-the olfactory epithelium. The investigator will determine whether interactions between the mesenchyme and the adjacent forebrain or surface epithelia are necessary for patterned gene expression and neuronal differentiation in the presumptive olfactory epithelium and forebrain. The contributions of four established inductive signaling molecules will be assessed. Retinoic Acid (RA), sonic hedgehog (shh), Fibroblast Growth Factor 8 (FGF8) and Bone Morphogenetic Protein 4 (BMP4) are all found in discrete cell populations in or around the forebrain, surface epithelium and mesenchyme. The investigator will analyze whether the presumptive olfactory epithelium or frontonasal mesenchyme provide unique signals to initiate morphogenesis and differentiation of olfactory structures. Finally, he will evaluate the extent to which inductive interactions influence the initial patterning of axonal projections between the olfactory epithelium and the forebrain. These experiments will therefore define a cellular and molecular basis for induction during regional and pathway development in the mammalian forebrain. The results will identify a major point of vulnerability of the developing forebrain to a range of environmental toxins, pharmacological agents, and genetic diseases. Such disruptions of early induction during forebrain development may ultimately compromise the unique behavioral and cognitive functions that are the province of distinct forebrain regions and circuits.