Cell migration is fundamental to normal central nervous system (CNS) development and perturbations in this process have been implicated in the pathogenesis of many neurologic disorders including epilepsy, mental retardation and autism. Understanding the pathogenesis of these all to common disorders requires, among other processes, the elucidation of the molecular and cellular mechanisms governing neuronal migration. Two primary pathways of cell migration are recognized during cerebral cortical development, radial and non-radial. At least in rodents, radial cell migration, from the pallial ventricular zone out to the cortical plate, gives rise to the projection neurons of the cerebral cortex, whereas cortical interneurons must travel along non-radial pathways from the subpallial proliferative zones to arrive in the cortical plate. Over the past five years, supported by this grant, we have made significant contributions to our understanding of interneuron migration. Over the next two years we plan to extend these studies to more clearly define the mechanisms governing non-radial cell migration in mammals. One fundamental questions is how does the leading process respond to guidance cues to direct the migrating interneurons from the ganglionic eminence along their circuitous path and finally into the cerebral cortex. We have hypothesis that the leading process functions like a growth cone by dynamically regulating its cytoskeleton in response to long and shortrange cues. Herein we propose to define the cytoskeletal dynamics in the migrating leading processes and establish how they are regulated by guidance cues (aim 1) and determine how Lis1 effects leading process dynamics (aim 2). Together these data will establish the cellular mechanisms by which the leading process is able to lead the migrating interneuron, an integral component of normal brain development and one that is disrupted in many neurologic disorders.

Public Health Relevance

Epilepsy and mental retardation co-exist in many children and together extract a significant financial burden on the US health care dollar, an estimated $51.2 billion (in 2003 dollars). Although 3-5% of all children in the United States exhibit epilepsy and/or mental retardation, the underlying pathogeneses for these disorders is poorly understood in most cases. The data from our previous work and from that proposed in this application will provide new insights into the pathogenesis of a variety of conditions afflicting children, ultimately leading to improvements in their diagnosis, treatment, and prevention of these and related neurologic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045034-07
Application #
7915803
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Riddle, Robert D
Project Start
2003-02-15
Project End
2011-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
7
Fiscal Year
2010
Total Cost
$370,125
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lysko, Daniel E; Putt, Mary; Golden, Jeffrey A (2014) SDF1 reduces interneuron leading process branching through dual regulation of actin and microtubules. J Neurosci 34:4941-62
Sunnen, C Nicole; Simonet, Jacqueline C; Marsh, Eric D et al. (2014) Arx is required for specification of the zona incerta and reticular nucleus of the thalamus. J Neuropathol Exp Neurol 73:253-61
Moore, Katherine D; Chen, Renee; Cilluffo, Marianne et al. (2012) Lis1 reduction causes tangential migratory errors in mouse spinal cord. J Comp Neurol 520:1198-211
Judkins, Alexander R; Martinez, Daniel; Ferreira, Pamela et al. (2011) Polymicrogyria includes fusion of the molecular layer and decreased neuronal populations but normal cortical laminar organization. J Neuropathol Exp Neurol 70:438-43
Lysko, Daniel E; Putt, Mary; Golden, Jeffrey A (2011) SDF1 regulates leading process branching and speed of migrating interneurons. J Neurosci 31:1739-45
Cho, Ginam; Lim, Youngshin; Golden, Jeffrey A (2011) XLMR candidate mouse gene, Zcchc12 (Sizn1) is a novel marker of Cajal-Retzius cells. Gene Expr Patterns 11:216-20
Gopal, Pallavi P; Simonet, Jacqueline C; Shapiro, William et al. (2010) Leading process branch instability in Lis1+/- nonradially migrating interneurons. Cereb Cortex 20:1497-505
Cho, Ginam; Lim, Youngshin; Golden, Jeffrey A (2009) SUMO interaction motifs in Sizn1 are required for promyelocytic leukemia protein nuclear body localization and for transcriptional activation. J Biol Chem 284:19592-600
Marsh, Eric D; Minarcik, Jennifer; Campbell, Kenneth et al. (2008) FACS-array gene expression analysis during early development of mouse telencephalic interneurons. Dev Neurobiol 68:434-45
Gopal, Pallavi P; Golden, Jeffrey A (2008) Pax6-/- mice have a cell nonautonomous defect in nonradial interneuron migration. Cereb Cortex 18:752-62

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