Malformations of cortical development due to disorder of neuronal migration are increasingly recognized as a common cause of epilepsy, mental retardation, and cerebral palsy. The doublecortin (DCX) gene is critical for neuronal migration in humans, as mutations result in X- linked lissencephaly in males and double cortex in females, producing severe neurocognitive deficits. We identified the DCX gene and found mutations in patients with this condition. We identified its role as a microtubule-associated protein (MAP) and its involvement in critical signaling pathways through phosphorylation- and dephosphorylation-dependent mechanisms. We uncovered important cellular roles for Dcx in cells, including mediation of nuclear-centrosome coupling, organization of microtubule condensation at the neurite """"""""wrist"""""""" and a requirement in adult stem cell migration. Dcx is part of a gene family also containing Dclk1 and Dclk2, each encoding a strongly brain-expressed protein with a closely matching Dcx domain and kinase domain. We found that Dcx;Dclk1 knockouts displays severe cortical neuronal migration defects that mirror lissencephaly, whereas Dcx;Dclk2 knockouts displays severe seizures, also part of the clinical picture of lissencephaly. However, the role of the kinase activities in neuronal development are unknown. The overall goal of this renewal application is to elucidate the signaling mechanisms of the Dcx gene family in neuronal development and brain function. We will utilize knockout and knock-in and genetic rescue experiments in mice combined with advanced live-cell imaging capabilities and in vivo analysis that will synergize to provide a powerful approach to address these goals.

Public Health Relevance

The doublecortin gene family plays critical roles in brain development, resulting in severe forms of epilepsy and mental retardation when mutated. We will study the signaling mechanisms of the doublecortin gene family, in order to understand the basis of these human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041537-12
Application #
8540459
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Riddle, Robert D
Project Start
2001-04-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
12
Fiscal Year
2013
Total Cost
$241,863
Indirect Cost
$76,365
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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