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 #
1R21MH101688-01A1
Application #
8702810
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
2014-03-15
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$236,500
Indirect Cost
$86,500
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143