Regional Differentiation During Forebrain Development

描述（由申请人提供）：前脑中的神经前体规范仍然知之甚少，尽管这些前体产生的神经元构成了认知、学习和记忆的基本电路。前脑前体的最初规范可能依赖于外部来源的信号，这些信号建立了内在的组织中心，并调节了随后的模式和分化。然而，这些外部来源的身份仍然不确定，它们对明确的前脑腹侧和背侧组织中心的影响尚不清楚。我们已经表明，神经嵴源性额鼻间质（FnM）和相邻前脑神经上皮之间的诱导信号影响前脑早期模式、信号分子的表达和随后的前体多样性。在本项目的Specific Aim 1中，我们将确定fnm介导的诱导是否明确指定于前脑模式，并促进前脑神经元的区域适当分化。FnM不太可能是前脑前体外部感应信号的唯一来源。我们的初步观察表明，FnM与另一个很少被考虑的前脑早期发育信号分子来源一致：前神经管打开时羊水（AF）中的可溶性蛋白和前神经管关闭后脑脊液（CSF）中的可溶性蛋白。我们发现房颤和脑脊液对神经发生能力、区域特性和随后的前脑前体增殖的支持存在差异。在Specific Aim 2中，我们将评估房颤和脑脊液中特定候选信号的活性，以及它们与fnm一起对前神经管关闭前神经上皮特性的影响，以及神经管关闭后径向胶质分化和腹侧和背侧前体区分的影响。最后，维甲酸（RA）作为FnM和AF/CSF对发育中的前脑的影响的重要方面的候选信号被发现。在早期阶段，FnM产生作用于前脑前体亚群的类风湿性关节炎。随后，脑膜合成作用于前脑祖细胞的类风湿性关节炎。在Specific Aim 3中，我们确定了这些多种RA来源在早期前脑模式和前体分化的不同步骤中的特异性，以及初始RA信号传导对前脑前体多样性和命运的影响。总之，我们的具体目标实验将首次定义外部诱导在前脑区域（包括嗅球、基底神经节和大脑皮层）建立前体、神经元和回路多样性的具体贡献。我们的研究结果将为一些疾病的大脑发育中断提供新的见解，这些疾病也会导致面部、心脏和肢体发育异常——所有这些疾病都依赖于类似于fnm介导的诱导机制——包括自闭症、唐氏综合征、智力迟钝和精神分裂症。

DESCRIPTION (provided by applicant): Neural precursor specification in the forebrain remains poorly understood, even though these precursors give rise to neurons that constitute essential circuitry for cognition, learning and memory. The initial specification of forebrain precursors is likely to rely upon signals from extrinsic sources that establish intrinsic organizing centers and regulate subsequent patterning and differentiation. The identity of such extrinsic sources, however, remains uncertain, and their influence on well-defined ventral and dorsal forebrain organizing centers is unknown. We have shown that inductive signaling between neural crest-derived frontonasal mesenchyme (FnM) and adjacent forebrain neuroepithelium influences early patterning, expression of signaling molecules, and subsequent precursor diversity in the forebrain. In Specific Aim 1 of this project we will determine whether this FnM-mediated induction is distinctly specified for forebrain patterning and facilitates regionally appropriate differentiation of forebrain neurons. It is unlikely that FnM is the sole source of extrinsic inductive signals for forebrain precursors. Our preliminary observations indicate that FnM acts in concert with another rarely considered source of signaling molecules available to the forebrain during early development: soluble proteins in the amniotic fluid (AF) when the anterior neural tube is open, and cerebrospinal fluid (CSF) once the anterior neural tube has closed. We have found that AF and CSF differentially support neurogenic capacity, regional identity, and subsequent proliferation of forebrain precursors. In Specific Aim 2, we will evaluate the activity of specific candidate signals in AF and CSF, and their effects-in concert with FnM-on neuroepithelial identity prior to anterior neural tube closure, as well as radial glial differentiation, and ventral and dorsal precursor distinctions once the neural tube closes. Finally, one molecule: retinoic acid (RA) has emerged as a candidate signal for essential aspects of FnM as well as AF/CSF influences on the developing forebrain. At early stages the FnM produces RA that acts on subsets of forebrain precursors. Subsequently, the meninges synthesize RA that acts on forebrain progenitors. In Specific Aim 3, we determine the specificity of these multiple RA sources for distinct steps in early forebrain patterning and precursor differentiation, as well as the consequences of initial RA signaling for forebrain precursor diversity and fate. Together, the experiments in our Specific Aims will define for the first time the specific contributions of extrinsic induction for establishing precursor, neuronal and circuit diversity in forebrain regions including the olfactory bulb, basal ganglia, and cerebral cortex. Our results will provide new insight into disrupted brain development in several disorders that also result in anomalous face, heart and limb development-all of which rely upon inductive mechanisms similar to that mediated by FnM-including autism, Down syndrome, mental retardation, and schizophrenia. PUBLIC HEALTH RELEVANCE: In behavioral disorders like autism, mental retardation, and psychiatric diseases like schizophrenia, abnormal brain function is thought to reflect disrupted early development of forebrain neurons and circuits. Understanding the role of signals that act on the developing forebrain, and how disrupting these signals changes the identity and fate of forebrain stem cells, is essential for defining pathogenic mechanisms in these increasingly prevalent diseases of forebrain development and function.