Downstream Effectors of Shh and FGF Signaling in the Developing Neocortex

描述(申请人提供)：皮质中间神经元是一个极其多样化的细胞群体，其功能障碍与许多复杂的神经疾病有关，包括癫痫、自闭症和精神分裂症。尽管已经了解了端脑的早期模式，通过声波刺猬(Shh)和成纤维细胞生长因子(FGF)信号建立，但对负责建立神经元间多样性的下游效应器知之甚少(Hebert&Fishell，2008)。最近，Fishell实验室进行了微阵列筛选，通过该筛选，确定了已知在大脑皮层下建立模式的两个外部信号(成纤维细胞生长因子和Shh)之一的许多候选下游效应器(Batista-Brito等人，2008年)。这样选择的基因之一是HMG-box转录因子Sox6。初步数据表明，Sox6在中间神经元中表达，并对建立中间神经元的某些亚群至关重要。SOX6‘S在神经元间发育中的作用将通过条件基因敲除方法与各种神经元间特异性和时间诱导的Cre驱动株相结合来阐明。为了补充对Sox6的研究，Sox6可能是Shh信号的下游效应者，也将调查成纤维细胞生长因子信号的下游效应者。这一原理导致了两个转录激活子ets1和ets2的发现。这些基因是高度保守的ETS超家族的成员，是已知的成纤维细胞生长因子信号的下游效应器(Tekki-Kessaris，N等，2001)。利用伯纳姆研究所的Oshima博士开发的ets2条件基因敲除，将产生一个发育中的中枢神经系统(CNS)特异的ets2基因敲除，以研究其对神经元间多样性和神经功能的要求。在与西奈山的Jean Hebert的合作中，将通过分析FGFR1/2双基因敲除小鼠来检验ets1和ets2在成纤维细胞生长因子信号下游发挥作用的假设。这些研究将通过使用包括免疫组织化学、电生理学和脑电(EEG)在内的各种技术来完成。这些研究的目的是确定Sox6和Ets1和2作为早期模式信号的下游效应因子在建立皮层神经元间多样性中的作用。与公共健康相关：这项工作将调查确定的基因，以确定它们在大脑抑制神经元发育中的可能作用。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.