DEFINING THE FUNCTION OF GBX 2 IN FOREBRAIN DEVELOPMENT

University Of California San Francisco, San Francisco CA

Investigators

Abstract

DESCRIPTION (Applicant's abstract reproduced verbatim): The etiologies of childhood brain abnormalities; such as epilepsy, mental retardation, and cerebral palsy, have been difficult to investigate because basic mechanisms of forebrain development are poorly understood. However, candidate regulatory genes, which have restricted expression patterns in the primordia of major forebrain regions, have been discovered recently. Elucidating the role of these genes will provide insights into the molecular mechanisms of forebrain development, which is the long term goal of this application. One candidate homeobox gene, is called Gbx-2. Mice deficient for Gbx 2 have abnormal thalamic development and lack thalamocortical innervation. Consequently, the focus of this application is to use the Gbx-2 mutant to understand thalamic development and the role thalamocortical innervation has on, which will be further investigated by analyzing, thalamic cell proliferation, migration, apoptosis, differentiation, and nuclei formation which will be assessed by birthdating studies, and cell type or nuclei specific gene expression by either in situ hybridization or immunohistochemistry. The Gbx 2 mutant also fails to develop proper thalamocortical innervation. Thus, lamination, cell maturation, and projections will be examined in mutant neocortex, using the same techniques listed above and DiI analysis to examine projections. Lastly, the boundaries of regionally expressed genes in the neocortex will be examined postnatally by in situ hybridization and correlated with assays, such as Nissl and myelin stains, cytochrome oxidase, and serotonin immunohistochemistry, which define functional subdivisions. If survival of Gbx 2 mutants can be prolonged, postnatal regionalization in the neocortex will be examined by in situ hybridization.