International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

G4 An Early Block to Telencephalic Development in Flat-Top Mutant Mice

Kathryn Hentges and Andrew Peterson. Duke University Medical Center

The telencephalic vesicles form in the mouse embryo by the expansion of precursor regions in the anterior neural tube. After the vesicles expand they undergo regionalization to form distinct dorsal and ventral territories. Since the processes that control expansion and regionalization are not well understood, we have performed a genetic screen to identify mutations that disrupt these processes. We first injected male mice with ENU, a chemical mutagen. The offspring were then crossed to uncover recessive mutations that affect forebrain development. One mutant isolated in the screen, Flat-top, has defects in the formation of the telencephalic vesicles, their regionalization, and the maintenance of gene expression. The Flat-top telencephalic vesicles do not expand during development due to a failure to increase cell proliferation in the forebrain neurectoderm. Regionally restricted genes such as Pax-6 and Nkx2.1 are not properly expressed in the Flat-top mutant. Additionally, the Flat-top mutant does not maintain ventral forebrain expression of BF-1 and Shh. Based on these studies we propose that the Flat-top gene is necessary for three aspects of telencephalic development: the expansion of the telencephalic vesicles, the regionalization of the telencephalon, and the maintenance of gene expression in the developing telencephalon.

Approximately 2500 meioses were analyzed to map the Flat-top locus to a 0.3cM interval on mouse chromosome 4, in a region of synteny with human chromosome 1. A mouse-human comparative map of the Flat-top region was generated by radiation hybrid mapping of genes in the Flat-top region. A BAC and PAC contig of the Flat-top region has been assembled, and efforts to positionally clone the Flat-top gene are ongoing.

 


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