Developmental failures in neuronal migration in the cerebral cortex result in epilepsy and mental retardation. Moreover, disorders in neural development account for a broad set of neurological diseases. Positional cloning has led to the identification of human genes mutated in periventricular heterotopia (PH), a malformation of cortical development characterized by the failure of a subset of neurons to migrate from the ventricle during cerebral cortical development. Mutations in either of two genes, the actin-binding filamin A (FLNA) and the vesicle transport related ARFGEF2, leads to severe defects in the initial migration of neurons along the ventricular lining and produces nearly identical radiographic findings of PH in humans. Mutations in the Napa gene in mice also lead to heterotopic nodules strikingly similar to those seen in humans. The central hypothesis of this application is that these common mutant phenotypes result from direct interactions between the encoded proteins or from a shared common pathway. The proposed functions of FLNA and ARFGEF2 appear quite disparate with FLNA implicated in neuronal motility due to its interactions with the actin cytoskeleton and BIG2 (encoded by ARFGEF2) involved in vesicle trafficking through its guanine exchange regulation of the ADP-ribosylation factors (ARFs). ARF activation is required during the assembly of protein coats for vesicle budding. Alpha-SNAP (encoded by Napa) is a NSF attachment protein, involved in SNAP receptor-mediated vesicle fusion. Collectively, however, all of these genes are involved in endosomal vesicle trafficking, either through regulation of actin filaments needed for transport, assembly of the coat protein, or fusion of the vesicle to the membrane. Thus, the role of FLNA and ARFGEF2 in giving rise to PH may share a common pathogenic mechanism with Napa by control over endosomal vesicle transport. Therefore the Specific Aims of this proposal are to determine: 1) which cellular defects seen following loss of FLNA function in mice contribute to PH formation, 2) whether FLNA binds BIG2 and directs BIG2 localization and BIG2-dependent ARF activation, and 3) whether loss of Napa or ARFGEF2 function in neural progenitors alters apical and/or basal adherens junctions leading to PH formation.

Public Health Relevance

Human mutations in several genes are known to cause nearly identical brain malformations and result in epilepsy and mental retardation. The current proposal seeks to understand the cellular and molecular mechanisms of these genes, and how their function might be interrelated given their shared phenotype. Understanding the pathophysiology of human brain disorders provides a means for the development of therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS063997-01A1
Application #
7729307
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Riddle, Robert D
Project Start
2009-06-01
Project End
2014-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
1
Fiscal Year
2009
Total Cost
$297,500
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Sheen, Volney L (2014) Filamin A and Big2: a shared endocytic pathway. Bioarchitecture 4:53-7
Hu, Jianjun; Lu, Jie; Lian, Gewei et al. (2014) Filamin B regulates chondrocyte proliferation and differentiation through Cdk1 signaling. PLoS One 9:e89352
Sheen, Volney L (2014) Filamin A mediated Big2 dependent endocytosis: From apical abscission to periventricular heterotopia. Tissue Barriers 2:e29431
Hu, Jianjun; Lu, Jie; Lian, Gewei et al. (2014) Formin 1 and filamin B physically interact to coordinate chondrocyte proliferation and differentiation in the growth plate. Hum Mol Genet 23:4663-73
Zhang, Jingping; Neal, Jason; Lian, Gewei et al. (2013) Filamin A regulates neuronal migration through brefeldin A-inhibited guanine exchange factor 2-dependent Arf1 activation. J Neurosci 33:15735-46
Sheen, Volney L; Shankar, Maithreyi; Marin-Valencia, Isaac et al. (2013) Methylphenidate and continuous spike and wave during sleep in a child with attention deficit hyperactivity disorder. Pediatr Neurol 49:54-7
Sheen, Volney; Valencia, Isaac M; Torres, Alcy R (2013) Atypical features in MECP2 P152R-associated Rett syndrome. Pediatr Neurol 49:124-6
Lu, Jie; Lian, Gewei; Zhou, Hui et al. (2012) OLIG2 over-expression impairs proliferation of human Down syndrome neural progenitors. Hum Mol Genet 21:2330-40
Sheen, Volney L (2012) Seizure or syncope: lessons over time. J Clin Neurosci 19:481-3
Zhang, Jingping; Neal, Jason; Lian, Gewei et al. (2012) Brefeldin A-inhibited guanine exchange factor 2 regulates filamin A phosphorylation and neuronal migration. J Neurosci 32:12619-29

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