Early Events in Cortical Development

描述（由申请人提供）：新皮层是大脑皮层的最大区域，处理感官信息，引起感知、意志运动反应和复杂现象，如学习和记忆。 这些不同的功能由新皮层的专门“区域”执行，其特征在于独特的连接和架构。这个项目的持续目标是定义和研究指导哺乳动物新皮层的解剖学，连接和功能组织的发育机制，以及将其分割成区域。新皮层区域的规范和分化可能是由新皮层内在的遗传调节和外部影响（如丘脑皮层（TCA）输入，从背侧丘脑的主要感觉核传递感觉信息）之间的相互作用控制的。最近的一个主要进展是通过对Emx 2和Pax 6（Sey/Sey）突变体的功能分析，证明了区域化的遗传调节涉及转录因子EMX 2和PAX 6。然而，EMX 2和PAX 6的这种作用只能从皮质中用作位置标记的基因的模式表达的变化中推断出来，因为这些突变体在P0死亡，远在区域在解剖学和功能上被定义之前。TCA输入的作用主要局限于发现标记基因的胚胎模式在缺乏TCA的情况下是正常的，也是有限的，因为缺乏TCA的可用突变体在P0死亡。因此，调节面积化的机制仍不明确。我们的目标是确定EMX 2和PAX 6作为内在调节因子的充分性和要求，TCA输入作为外在影响。我们将使用功能获得（转基因）和功能丧失（条件性敲除）分析以及遗传细胞消融，使用组织特异性基因激活/失活方法在设计为成年小鼠中测试我们的假设。我们将分析皮质神经元的区域特异性表型，包括位置标识标记的表达，区域特异性输入和输出投射，以及新皮质的解剖和功能组织。多层次的分析和替代战略的建议，将规避与更有限的方法相关的潜在问题，提供补充的调查结果，以证实的解释和进一步的见解调节的实现。我们期望发现支持我们假设的结果，但实验的设计使得反驳我们假设的结果同样具有信息性。

DESCRIPTION (provided by applicant): The neocortex, the largest region of the cerebral cortex, processes sensory information giving rise to perception, volitional motor responses, and to complex phenomena such as learning and memory. These distinct functions are performed by specialized 'areas' of the neocortex, characterized by unique connectivity and architecture. The continuing objective of this project is to define and study developmental mechanisms that direct the anatomical, connectional, and functional organization of the mammalian neocortex, and its parcellation into areas. The specification and differentiation of neocortical areas is likely controlled by interplay between genetic regulation intrinsic to the neocortex and extrinsic influences such as thalamocortical (TCA) input that relays sensory information from the principal sensory nuclei of dorsal thalamus. A major recent advance is evidence for the genetic regulation of arealization that implicates the transcription factors EMX2 and PAX6 by loss of function analysis of mutants for Emx2 and Pax6 (Sey/Sey). However, this role for EMX2 and PAX6 is only inferred from changes in the patterned expression of genes used as positional markers in cortex because these mutants die on P0, well before areas become anatomically and functionally defined. The role of TCA input, which has been mainly limited to the finding that embryonic patterning of marker genes is normal in the absence of TCAs, is also limited because the available mutants that lack TCAs die at P0. Thus, mechanisms regulating arealization remain poorly characterized. Our goal is to define the sufficiency and requirements for EMX2 and PAX6 as intrinsic regulators, TCA input as an extrinsic influence, We will test our hypotheses using gain of function (transgenic) and loss of function (conditional knockouts) analyses, as well as genetic cell ablations, using tissue-specific gene activation / inactivation approaches in mice designed to live to be adults. We will analyze the area-specific phenotypes of cortical neurons, including expression of markers of positional identity, area-specific input and output projections, and the anatomical and functional organization of the neocortex into areas. The multilevel analyses and alternative strategies proposed will circumvent potential problems associated with more limited approaches, provide complementary findings to substantiate interpretations and further insights into the regulation of arealization. We expect findings that support our hypotheses, but the experiments are designed such that results that disprove our hypotheses will be equally informative.