GENE AND TRANSGENE REGULATION IN THE DEVELOPING MOUSE

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Murine LIM-homeobox genes involved in the development of central nervous and neuroendocrine tissues. This gene family encodes regulators of development that play pivotal roles in pattern formation and cell specification during metazoan development. Their products contain two N- terminal cysteine-rich motifs, the LIM domains, and an adjacent homeodomain. This group has cloned and sequenced murine homologs of the Xenopus laevis genes XLIM1, XLIM2 and XLIM3. The degree of homology is very high. LIM1 expression in the developing mouse embryo begins during gastrulation and later homes in on the central nervous system from the telencephalon through the spinal cord, and on the developing excretory system. The LIM3 gene is expressed in the developing pituitary gland, in the ventral hindbrain and the ventral spinal cord. The pattern of LIM2 expression is currently under investigation. Also, deletions in two murine lim genes have been generated in the mouse germline in an effort to study their mechanism of action during mouse development. Effects of human p53 expression on murine lens development. The wild- type human p53 gene causes microphthalmia when targeted to the developing embryonic lens in the transgenic mouse. This phenotype is due to a defect in secondary fiber differentiation that sets in shortly after birth. By contrast, lens development is almost unaffected by the expression of a mutant human p53 that is impaired in DNA binding. The phenotype caused by the wild-type human p53 gene can be rescued by the mutant allele, possibly via a mechanism of dominant negative interference. The results have implications for schemes of p53 gene therapy in patients. Altered striatal functions in a mutant mouse lacking D1A dopamine receptors. Mice homozygous for the deletion carry D1A striatal neurons that are totally devoid of functional D1A receptors. The animals die shortly after weaning unless their diet is supplemented with hydrated food. Although locomotion appears unaffected, the mice display a significant decrease in rearing behavior. Details of the involvement of D1A dopamine receptors in the pathogenesis of Parkinson's disease and schizophrenia, and their role in cocaine and amphetamine addiction can be analyzed with the help of this mouse strain.