Disruption in neuronal migration results in severe neurological and developmental impairments such as cognitive deficits and epilepsy that are recognized primarily in the pediatric population. A signaling pathway crucial for proper neuronal migration and brain development is initiated by the evolutionarily conserved glycoprotein Reelin. Human mutations in the Reelin pathway generate phenotypes that mimic those induced by mutations in cytoskeletal proteins that disrupt the function of microtubules and actin. The culmination of these genetic studies in children strongly suggests that several signaling pathways including the Reelin pathway converge on downstream cytoskeletal proteins to affect proper neuronal migration, brain development and cognition. We used a systems biology approach to identify the microtubule-stabilizing CLASP2 as a key cytoskeletal modifier of Reelin signaling. We previously found that CLASP2 regulates several important phenotypes during neuronal development in vitro including Golgi morphology, neuronal branching, axon specification and synaptic activity, phenotypes that are also regulated by Reelin signaling. However, little is known about the role of CLASP2 and its association with the Reelin signaling pathway in the developing brain. Therefore, our goal is to understand how Reelin signaling regulates CLASP2-mediated cytoskeletal function during neuronal and brain development. In the first aim, we will define the interaction of CLASP2 with Dab1, a downstream node in the Reelin pathway, and then determine the functional consequences of this interaction. In the second aim, we will define the in vivo function of CLASP2 during brain development. The proposed studies aim to advance the understanding of how Reelin controls neuronal migration through cytoskeleton reorganization, key elements of normal brain development.

Public Health Relevance

Brain development is a complex process that involves the movement and proper connectivity of neurons. Mutations in certain genes lead to improper neuron movement and brain development that often lead to severe learning disabilities in children. We are studying a specific pathway tha controls one aspect of neuron movement and brain development. A better understanding of the molecular mechanism of how genes affect neuronal migration and development will eventually lead to advances in diagnosis and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH100581-01A1
Application #
8638557
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Panchision, David M
Project Start
2013-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$245,550
Indirect Cost
$95,550
Name
Boston University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215