Our brains function through complex and dynamic networks of interconnected neurons. Understanding how this neuronal circuitry is established and regulated is not only the central question of neuron development studies, but also the key to understand the pathogenesis of neurodevelopment disorders. In the aCC motoneuron of Drosophila embryo, our preliminary findings have hinted the connection among the Down syndrome cell adhesion molecule (Dscam1), cytoskeleton activity regulators including Cdc42 effectors, and the positioning and initiating of dendrite growth. Therefore, we hypothesize that Dscam intercellular interaction promotes and positions aCC dendritogenesis through membrane enrichment of Cdc42 effectors. We plan to test this hypothesis using a combination of genetic and super-resolution microscopy methods. Our project consists of three aims:
Aim 1 to examine the role of Cdc42 effector membrane accumulation in controlling the position of new dendrites, Aim 2 to elucidate the mechanism for Dscam in aCC to guide the positioning of Cdc42 effectors, and Aim 3 to understand the extracellular cue from partner neurons through Dscam1-Dscam1 interaction. Accomplishing these aims will provide insights into the detailed molecular mechanisms of Dscam function, especially how cell-cell recognition is translated through cytoskeleton dynamics into neuron morphogenesis in CNS, which has been very much under-explored in the central nervous system (CNS).

Public Health Relevance

brains function through complex and dynamic networks of interconnected neurons. Understanding how this neuronal circuitry is established and regulated is not only the central question of neuron development studies, but also the key to understand the pathogenesis of neurodevelopment disorders such as autism, fragile-X syndrome and Down syndrome. Our proposed research work could elucidate new principles for establishing neuronal circuitry, and a signaling pathway potentially linked to the pathogenesis of Down syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH101688-02
Application #
8821674
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Panchision, David M
Project Start
2014-03-15
Project End
2016-02-29
Budget Start
2015-03-01
Budget End
2016-02-29
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Kelliher, Michael T; Yue, Yang; Ng, Ashley et al. (2018) Autoinhibition of kinesin-1 is essential to the dendrite-specific localization of Golgi outposts. J Cell Biol 217:2531-2547
Kamiyama, Daichi; Sekine, Sayaka; Barsi-Rhyne, Benjamin et al. (2016) Versatile protein tagging in cells with split fluorescent protein. Nat Commun 7:11046
Leonetti, Manuel D; Sekine, Sayaka; Kamiyama, Daichi et al. (2016) A scalable strategy for high-throughput GFP tagging of endogenous human proteins. Proc Natl Acad Sci U S A 113:E3501-8
McGorty, Ryan; Liu, Harrison; Kamiyama, Daichi et al. (2015) Open-top selective plane illumination microscope for conventionally mounted specimens. Opt Express 23:16142-53
Kamiyama, Daichi; McGorty, Ryan; Kamiyama, Rie et al. (2015) Specification of Dendritogenesis Site in Drosophila aCC Motoneuron by Membrane Enrichment of Pak1 through Dscam1. Dev Cell 35:93-106