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种非常多样化的细胞群，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。尽管我们通过超音hedgehog基因（Shh）和成纤维细胞生长因子（FGF）信号传导了解了端脑的早期模式，但对负责建立中间神经元多样性的下游效应物知之甚少（Hebert & Fishell, 2008）。最近，Fishell实验室进行了一项微阵列筛选，通过该筛选确定了已知在皮层下建立模式的两种外部信号（FGF和Shh）的众多候选下游效应物（Batista-Brito等人，2008）。其中一个被选中的基因是Sox6，一种HMG-box转录因子。初步数据表明Sox6在中间神经元亚群中表达，并对其建立起关键作用。Sox6在中间神经元发育中的作用将通过与各种中间神经元特异性和暂时诱导的Cre驱动系结合的条件敲除方法来阐明。为了配合对Shh信号的下游效应因子Sox6的研究，FGF信号的下游效应因子也将被研究。这一原理导致了两个转录激活因子的鉴定，ets1和ets2。这些基因是高度保守的ets超家族的成员，是已知的FGF信号的下游效应基因（Tekki-Kessaris, N et al., 2001）。利用伯纳姆研究所的Oshima博士开发的ets2条件敲除，将产生一个发育中的中枢神经系统（CNS）特异性敲除ets2，以研究其对中间神经元多样性和神经功能的要求。在与西奈山的Jean Hebert的合作中，通过分析FGFR1/2双敲除小鼠，ets1和2在FGF信号下游起作用的假设将得到验证。这些研究将通过使用各种技术来完成，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Sox6和Ets1和2的作用，作为早期模式信号的下游效应器，在皮层中建立中间神经元多样性。公共卫生相关性：这项工作将研究在大脑中抑制性神经元发育中可能起作用的基因。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.