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.
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.
