Genetic Studies of Cortex Structure and Development

Investigator: John L. Rubenstein, MD, PhD
Sponsor: NIH National Institute of Neurological Disorders and Stroke

Location(s): United States


I hypothesize that Fgf signaling from the rostral patterning center plays a major role in governing growth and patterning of the rostral telencephalon, including the frontal cortex. The experiments described below are designed to identify the molecular mechanisms that control: 1) Fgf expression and signaling; 2) how Fgfs, and other signals, regulate expression of enhancers that drive expression in the developing frontal cortex; 3) morphogenesis of the rostral telencephalon (frontal cortex and septum). The proposal has four Aims: Aim I. Characterize the fates of cells in the rostral patterning center. Aim II. Identify mechanisms that regulate gene expression in the rostral patterning center. Aim III. Investigate the regulation of frontal cortex patterning: identify and characterize enhancers that define subdivisions of the frontal cortex. Aim IV. Analyze roles of Fgf signal regulation in the rostral patterning center: analysis of Sprouty1, 2 and 1/2 mutants. I believe that these experiments will provide a firm foundation for elucidating the genetic, molecular, and cellular mechanisms that control development of the cerebral cortex and that may underlie some Human neurodevelopmental disorders such as Autism, Schizophrenia, and Epilepsy. Disruption of cerebral cortex development and function is strongly associated with several major neuropsychiatric disorders, including autism and schizophrenia. The experiments proposed in this application aim to elucidate basic mechanisms that underlie normal development of prefrontal cortex, an integral region subserving higher cognitive function. This information will provide a key foundation for understanding the genetic and molecular mechanisms underlying many psychiatric disorders.