Grant: $402,605 - National Institutes of Health - Sep. 15, 2009
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Award Description: Developmental defects of the cerebellum in humans have received less attention than other brainmalformations such as neural tube defects and cortical malformations. Yet, cerebellar malformations arecommon, affecting approximately 1/5000 births. Dandy-Walker Malformation (DWM) is the most frequentcerebellar malformation. Affected individuals often have motor deficits, mental retardation, autism and somehave hydrocephalus. Although the specific causes of this clinically important birth defect remain largelyundefined, there is evidence for considerable genetic heterogeneity and complex inheritance. Based onphysical mapping of chromosomal abnormalities in patients, we have identified 2 loci harboring human DWMon chromosomes 3q24 and 6p25. This proposal describes a series of experiments aimed at understandingthe developmental mechanisms leading to DWM pathology through the study of several mouse models. We have previously demonstrated that heterozygous co-deletion of the closely linked ZIC1/4 genes onchromosome 3q24 causes DWM. Aim 1 of this proposal describes a series of genetic experiments in Zic1/4mutant mice to assess the developmental pathways regulated by these Zic genes. The experiments in Aim 2are designed to define the basis of 6p25 DWM, through phenotypic characterization of both null andconditional mouse mutants of a candidate gene influencing both posterior fossa mesenchymal and cerebellardevelopment. Since similar mechanisms underlie both mouse and human CNS development, analysis of thesemice will to determine the underlying molecular and developmental causes of human DWM. This information iscritical to the identification of additional human DWM loci.
Project Description: AS DEFINED IN THE AWARD DESCRIPTION.
Jobs Summary: 0.15 clerical, 0.06 faculty, 0.42 research assistant, 0.33 research associate, 0.46 research technician (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on Sep. 15, 2009. Help expand these official descriptions using the wiki below.