The experiments outlined in this application, and our long term goals, seek to fill a large knowledge gap in our understanding of the developmental mechanisms that control neural circuit wiring. Our collaboration with Dr. Christopher Garcia at Stanford revealed two Ig superfamily subfamilies, the 9-member Dprs and 21-member DIPs. These cell surface proteins (CSPs) bind to one other in unique and overlapping patterns and are expressed on small and unique subsets of neurons in the Drosophila nervous system. The primary hypothesis underlying this application is that Dprs and their DIP partners control cell-cell interactions that underlie synaptic specificity in neural circuits. Our innovative approach is fueled by the Dpr-DIP interactome since we are able to systematically analyze synaptic partners that express corresponding Dpr and DIP partners. Relevant to this proposal, I have gathered preliminary data suggesting that a Dpr-DIP pair mediates synaptic targeting.
The first aim takes advantage of the accessibility and invariant connections of the larval neuromuscular junction to understand how interactions between this Dpr-DIP pair control the formation and targeting of a motor axon branch. The focus of the second aim is to examine the roles of Dpr-DIP interactions in neurite growth and the wiring of motor circuits in the ventral nerve cord. These studies will uncover basic principles governing neural circuit assembly and specifically, how CSP subfamilies contribute to this specificity. These analyses will utilize my training in Drosophila neural development and expertise in genetics, electrophysiology, microscopy, and morphological analyses. As a recently hired, tenure-track assistant professor at the University of Chicago, I will take full advantage of the interdisciplinary, collaborative environment to build a productive and independent career. An exceptional mentoring team, consisting of my mentor, Dr. Ilaria Rebay (UChicago), and co-mentors, Dr. Hugo Bellen (Baylor College of Medicine) and Dr. Benjamin White (NIMH), will evaluate my progress and provide feedback. Under this K01 award I will gain additional technical training and the skills required to create a rigorous, independent research program and compete for independent funding, including an R01. These experiences will lay the groundwork to obtain tenure and run a successful, well-funded laboratory.

Public Health Relevance

The results from this proposal will uncover fundamental molecular mechanisms that regulate neural circuit development. Although our work is conducted in Drosophila, there is a subfamily of human proteins that corresponds to the DIPs. These proteins, the IgLONs, function in neural circuit formation, and mutations and altered expression of IgLONs have been linked to cancer, obesity, and neurological diseases characterized by alterations in synaptic connectivity, including autism, schizophrenia, and dyslexia. Thus, our work may have translational impact on the understanding of human diseases due to the conservation of fundamentally important developmental mechanisms.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Scientist Development Award - Research & Training (K01)
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Neurological Sciences Training Initial Review Group (NST)
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Miller, Daniel L
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University of Chicago
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United States
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