LIM-HD Transcription Factors in Forebrain Patterning

前脑模式中的 LIM-HD 转录因子

• 批准号: 6983454
• 负责人: DENNIS D O'LEARY
• 金额: $ 43.87万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6983454
• 关键词: DNA binding protein; gene expression; genetic regulation; genetically modified animals; laboratory mouse; neocortex; neurogenetics; prosencephalon; regulatory gene; thalamocortical tract; thalamus; transcription factor

DESCRIPTION (provided by applicant): A fundamental principle that underlies the anatomical and functional organization of the adult mammalian forebrain is the patterning of the neocortex into distinct areas and the parcellation of the dorsal thalamus (dTh) into nuclei. The developmental patterning of the neocortex into areas, i.e. the process of arealization, is controlled by both intrinsic mechanisms, defined here as regulatory genes that specify positional or area identities of cortical neurons, and extrinsic influences, mainly considered to be area-specific thalamocortical axon (TCA) input, or the information being relayed by it, that arises from dTh nuclei and is established in part by the genetic framework intrinsic to the neocortex. Evidence for the intrinsic genetic regulation of arealization has only begun to emerge over the past few years and thus far has implicated the homeodomain transcription factor EMX2 and the paired-box transcription factor PAX6 in controlling arealization. Less is known about the genetic mechanisms that pattern the dTh into nuclei and specify nuclei-unique properties. We hypothesize that the LIM-homeodomain (LIM-HD) transcription factors LHX2 and LHX9 specify area identities in the cortex and nuclei identities in the dTh through a direct mechanism, based on the known functions of LIM-HD genes, the uniquely graded expression of LHX2 in the neocortex, and the combinatorial expression of LHX2 and LHX9 in subsets of dTh nuclei. We also propose that they indirectly, but critically, influence neocortical arealization by controlling patterning of the dTh into nuclei and specifying properties autonomous to dTh projection neurons that determine the development of their TCA projections to specific neocortical areas, which in turn influence cortical patterning. To study these roles for LHX2 and LHX9, we will employ a range of approaches including conditional gain- and loss-of-function analyses using tissue specific transgene expression and targeted gene inactivation in mice designed to survive to adulthood. We will analyze area- and nuclei-specific phenotypes of cortical and dTh neurons, including expression of markers of identity, specific input and output projections, and the organization of neocortex into areas and dTh into nuclei. The multilevel analyses and alternative strategies proposed will help circumvent potential problems associated with more limited approaches, provide complementary findings to support interpretations, and help establish a hierarchy of regulation of forebrain patterning.

描述（由申请人提供）：构成成年哺乳动物前脑解剖学和功能组织基础的基本原理是新皮质形成不同区域的模式和背侧丘脑（dTh）包裹成核。新皮层发育成区域的模式，即区域化的过程，由内在机制和外在影响控制，内在机制在这里被定义为指定皮层神经元的位置或区域身份的调节基因，外在影响主要被认为是区域特异性丘脑皮层轴突（TCA）输入，或由其传递的信息，它起源于dTh核，部分由新皮层固有的遗传框架建立。在过去的几年里，局部化的内在遗传调控的证据才开始出现，到目前为止，已经暗示同源结构域转录因子EMX 2和配对盒转录因子PAX 6在控制局部化。很少有人知道的遗传机制，图案的dTh到细胞核和指定核的独特属性。我们假设LIM-同源结构域（LIM-HD）转录因子LHX 2和LHX 9通过直接机制指定皮质中的区域身份和dTh中的核身份，基于LIM-HD基因的已知功能，LHX 2在新皮质中的独特分级表达，以及LHX 2和LHX 9在dTh核亚群中的组合表达。我们还建议，他们间接地，但至关重要的是，通过控制图案的dTh到核和指定属性自主的dTh投射神经元，确定他们的TCA预测发展到特定的新皮层区域，这反过来又影响皮层图案的新皮层区域化。为了研究LHX 2和LHX 9的这些作用，我们将采用一系列方法，包括使用组织特异性转基因表达和靶向基因失活在小鼠中生存到成年期的条件性获得和功能丧失分析。我们将分析皮质和dTh神经元的区域和核特异性表型，包括身份标记物的表达，特定的输入和输出投射，以及新皮质到区域和dTh到核的组织。多层次的分析和替代策略的建议将有助于规避潜在的问题与更有限的方法，提供补充的研究结果，以支持解释，并帮助建立一个层次的前脑模式的调节。