Roles of Gsh1 &2 genes in telencephalic neurogenesis

Children'S Hospital Med Ctr (Cincinnati), Cincinnati OH

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Abstract

DESCRIPTION (provided by applicant): The telencephalon represents the region of the brain most concerned with cognition and voluntary movement. Two of the major telencephalic regions controlling these processes are the cerebral cortex and the striatum (also known as the caudate-putamen). Malfunction of these regions occurs in a number neurodegenerative disorders such as Parkinson's disease and Huntington's chorea, leading to abnormal movements and in some cases dementia. Moreover, certain neurodevelopmental disorders, such as Schizophrenia, Tourette's syndrome and autism are believed to result from malfunction and/or altered development of the cerebral cortex and striatum. Thus understanding the development of these telencephalic brain regions is likely to be of considerable importance to the diagnosis and/or treatment of these disorders.Regional development along both the anterior/posterior and dorsal/ventral axes of the developing telencephalon is known to be controlled by the spatially and temporally restricted expression of developmental control genes. Many of these developmental control genes belong to the homeobox transcription factor subclass. Two such examples are the related genes Gsh1 and Gsh2, which encode for homeobox proteins and are required for normal development of distinct subregions in the telencephalon, diencephalon and hindbrain. Recent studies have demonstrated that Gsh2 is required for the normal development of the striatum and olfactory bulb. Homozygous loss-of-function mutants for Gsh2 possess a significantly smaller striatum and reduced numbers of olfactory bulb interneurons as compared to wild-type controls. These defects are caused by a misspecification of the striatal and olfactory bulb precursors in the Gsh2 mutants at early stages of neurogenesis. The striatal and olfactory bulb neurogenesis that does occur the Gsh2 mutants is likely due to the fact that the molecular specification of striatal projection neuron and olfactory bulb interneuron precursors normalizes at late stages of neurogenesis. Our recent results have shown that this delayed normalization depends on the function of Gsh1. Although Gsh1 homozygous mutants do not display obvious defects in striatal and olfactory bulb neurogenesis, this gene is essential for the development of these telencephalic regions in the Gsh2 mutant telencephalon.The experiments outlined in this proposal are aimed at better understanding the specific roles of Gshl and Gsh2 in the development of the striatum and olfactory bulb interneurons. Firstly, the role that Gsh genes play in retinoid metabolism and signaling will be studied using retinoid reporter assays as well as transgenic mice in which retinoid signaling has been blocked. Secondly, the functional equivalence of the GshI and Gsh2 will be tested in knock-in experiments where Gsh2 will be replaced with GshI using gene targeting as well as in embryonic transplantation studies using mutant cells. Finally, we will determine the spatial and temporal requirements for Gsh2 in striatal and olfactory bulb development using gene targeting and conditional mutagenesis.