Downstream Effectors of Shh and FGF Signaling in the Developing Neocortex

描述（由申请人提供）：皮质中间神经元是一个非常多样化的细胞群体，其功能障碍与许多复杂的神经系统疾病有关，包括癫痫、自闭症和精神分裂症。尽管了解端脑的早期模式，通过音刺猬（Shh）和成纤维细胞生长因子（FGF）信号传导建立，但对负责建立中间神经元多样性的下游效应子知之甚少（Hebert & Fishell，2008）。最近，Fishell实验室进行了微阵列筛选，通过该微阵列筛选，鉴定了已知在腭下神经中建立模式的两种外源信号（FGF和Shh）中任一种的许多候选下游效应物（Batista-Brito et al.，2008年）。这样选择的基因之一是Sox 6，一种HMG盒转录因子。初步数据表明，Sox 6表达在中间神经元的一些亚群中，并且对于建立中间神经元的一些亚群至关重要。Sox 6在中间神经元发育中的作用将使用条件性敲除方法结合各种中间神经元特异性和时间诱导型Cre驱动线来阐明。为了补充Sox 6（Shh信号传导的可能下游效应物）的研究，还将研究FGF信号传导的下游效应物。这个理论基础导致了两个转录激活因子的鉴定，ets 1和ets 2。这些基因是高度保守的ets超家族的成员，并且是已知的FGF信号传导的下游效应物（Tekki-Kessaris，N等人，2001年）。使用由Burnham研究所的Oshima博士开发的ets 2条件性敲除，将产生发育中的中枢神经系统（CNS）特异性ets 2敲除，以研究其对中间神经元多样性和神经功能的需求。与西奈山的Jean Hebert合作，将通过分析FGFR 1/2双敲除小鼠来测试ets 1和2在FGF信号下游工作的假设。这些研究将通过使用各种技术完成，包括免疫组织化学、电生理学和脑电图（EEG）。这些研究的目的是确定Sox 6和Ets 1和2的作用，作为早期模式信号的下游效应器，在建立皮层中的interneuron多样性。公共卫生相关性：这项工作将调查基因确定为他们在大脑中抑制性神经元的发展可能发挥的作用。人类这些神经元的异常功能或发育与多种复杂的神经系统疾病有关，包括癫痫、自闭症和精神分裂症。

DESCRIPTION (provided by applicant): Cortical Interneurons are an incredibly diverse population of cells whose dysfunction has been implicated in many complex neurological diseases, including epilepsy, autism and schizophrenia. Despite the understanding of the early patterning of the telencephalon, established though sonic hedgehog (Shh) and fibroblast growth factor (FGF) signaling, little is known about the downstream effectors responsible for establishing interneuron diversity (Hebert & Fishell, 2008). Recently the Fishell lab performed a microarray screen through which numerous candidate downstream effectors of either of the two extrinsic signals (FGF and Shh) known to establish pattern in the subpallium were identified(Batista-Brito et al., 2008). One of the genes thus selected was Sox6, an HMG-box transcription factor. Preliminary data suggests that Sox6 is expressed in and critical for establishing some subpopulations of interneurons. Sox6's role in interneuron development will be elucidated using a conditional knockout approach in conjunction with various interneuron specific and temporally inducible Cre driver lines. To compliment the investigation of Sox6, a likely downstream effector of Shh signaling, downstream effectors of FGF signaling will also be Investigated. This rationale led to the identification of two transcriptional activators, ets1 and ets2. These genes are members of the highly conserved ets superfamily and are known downstream effectors of FGF signaling (Tekki-Kessaris, N et al., 2001). Using the ets2 conditional knockout developed by Dr. Oshima of the Burnham institute, a developing central nervous system (CNS) specific knockout of ets2 will be generated to investigate its requirement for interneuron diversity and neurological function. In collaboration with Jean Hebert of Mount Sinai, the hypothesis that ets1 and 2 work downstream of FGF signaling will be tested by analyzing FGFR1/2 double knockout mice. These studies will be completed through the use of a variety of techniques including immunohistochemistry, electrophysiology, and electroencephalography (EEG). The aim of these studies is to identify the role of Sox6 and Ets1 and 2, as downstream effectors of early patterning signals, in establishing interneuron diversity in the cortex. PUBLIC HEALTH RELEVANCE: This work will investigate genes identified for their possible role in the development of inhibitory neurons in the brain. The abnormal function or development of these neurons in humans has been implicated in multiple complex neurological disorders, including epilepsy, autism and schizophrenia.