Mammalian development relies on precise temporal and spatial regulation of gene expression and cellular interactions. Cells are driven to proliferate, differentiate, migrate and die until they eventually form a diverse array of structures in the adult. The characterization of developmental mutants of Drosophila, C.elegans, and M.musculus have provided insights into how critical regulatory genes such as the homeobox and paired box-containing transcription factors control this process. The mouse mutant fidget (fi) is a single gene autosomal recessive mutation on mouse Chromosome 2 that displays specific abnormalities in the inner ear (semicircular canals), the eyes (retina and lens), the neural tube and several skeletal sites. These pleiotropic abnormalities range from striking to subtle and have features similar to various neurodevelopmental disorders in humans and mice. In addition, the fi mutation interacts with other mouse mutations, including splotch - encoded by the Pax3 paired-box gene, ocular retardation-encoded by the Chx10 homeobox gene, microphthalmia - encoded by the Mitf HLH transcription factor and the not cloned aphakia mutation. Although the fidget gene is not yet known, earlier studies suggested that at least its retinal and neural abnormalities are caused by reduced proliferation of progenitor cells due to prolongation of the G1 phase of the cell cycle. It is possible, though less clear, however, wheter delayed growth is the proximal cause of the other abnormalities of fidget mice or whether these result from secondary influences such as induction. The identification and characterization of the fidget gene will allow us to address and pursue these issues. Towards this end, we have developed a high resolution map by breeding, phenotyping and genotyping almost 1200 intersubspecific mice. The fidget mutation is now delimited to a critical interval of not more than 300 kb. Several known, developmentally-relevant candidate genes have already been excluded. The steps we will take to identify fidget will be 1) to reduce this interval even further, 2) to clone candidate cDNAs using a modified direct selection procedure, determine which is defective in fidget and characterize its expression, and 3) to confirm the candidate can correct the effects of the fidget mutation using transgenic mice. Once the gene is identified and the temporal and spatial sites of expression learned, the way will be paved for future studies where the fidget gene can be mutagenized and combined with other gene mutations in an informed fashion to explore the basis for its pleiotropic effects during development and its role in cell proliferation.
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