Regulation of Cortical Circuit Development by Sonic Hedgehog Signaling

Harvard Medical School, Boston MA

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Abstract

DESCRIPTION (provided by applicant): During development neurons in the cortex must navigate through a sea of potential partners in order make the proper synaptic connections required for functional circuitry. Understanding the cellular and molecular mechanisms involved in the specificity of connections is crucial to our ability address a myriad of neurological disorders such as autism, schizophrenia, and epilepsy, in which specific neuronal connections are altered in ways that prevent normal network function. The objective of this study is to understand how the secreted molecule Sonic Hedgehog functions to convey synaptic preferences during cortical development. Sonic Hedgehog (SHH) is a secreted molecule that has numerous critical functions during nervous system development. First as a morphogen regulating proliferation and dorsoventral patterning of the nervous system, and later as an axon guidance cue in the developing spinal cord and retina. Mutations of SHH in humans are associated with a broad range of clinical symptoms, ranging from severe malformation of the brain (holoprosencephaly) to milder learning disabilities and delays in speech acquisition. These genetic studies suggest that Shh function may not only be critical for the patterning of the nervous system, but also may have roles in human cortical circuit formation, and highlight our need to understand Shh function in the cortex during circuit development. Previously I've shown that Shh is expressed in specific populations of subcortical projection neurons located primarily in cortical layers V and VI, while the Sonic Hedgehog receptor Boc is expressed in a complementary population of local and colossal projection neurons. We further showed that Boc and Shh expression is required for the development of layer II/III to layer V synaptic connections. These results have lead us to hypothesize that neural cell type specific expression of Shh signaling components in the developing cortex is required for the development of specific cortical circuits. We propose to characterize the cell type specificity and cellular localization o Shh signaling components Shh, Ptch1, Smo, Boc, in the developing cortex. We will then assess the mechanism by which these components contribute to the development of cortical circuitry, and their dependence on noncanonical Shh signaling. Finally, we will test if expression of Shh and its cognate receptors are sufficient to alter the synaptic preferences of cortical neurons. In order to reach my ultimate goal of achieving tenure in the Department of Neurobiology at Harvard Medical School, I have developed a career development plan and formed a committee of mentors, consisting of tenured faculty in the department. Dr. Rosalind Segal will serve as my primary mentor, with the department chair, Dr. Michael Greenberg and tenured professor Dr. Wade Regehr serving as co-mentors. I have chosen each member of my mentoring committee because of their extensive track records of mentorship both at the laboratory and departmental level. I have also chosen this particular group because of their areas of scientific expertise, and the technical and scientific advice that I stand to gain from our mentoring relationship. My career development activities will be focused on three major aspects to my career success. 1) Mentorship and guidance focused on laboratory management and organization. 2) The development and growth of my independent research program. 3) Navigating institutional responsibilities and fulfilling requirements for promotion and tenure and expanding my scientific network and profile.