GENE AND TRANSGENE REGULATION IN THE DEVELOPING MOUSE

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Functional analysis of murine Lhx (LIM/homeobox) genes. 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. Our group has begun to characterize the function of murine members of the LIM/homeobox gene family. Ablation of the Lhx2 gene in the mouse germline has demonstrated that this gene is required for normal development of the eye and the cerebral cortex, and is also necessary for efficient definitive erythropoiesis. A similar approach has identified the Lhx3 gene as a function essential for the development of the anterior and intermediate lobes of the pituitary gland. Lhx5, a gene that we cloned most recently, appears to function prominently during forebrain formation. In a complementary effort to understand the mechanism of Lhx gene function, we cloned a novel gene encoding LBP, a peptide that binds the LIM domains of Lhx peptides and appears to play a synergistic role in Lhx function. Requirement for the Shh (sonic hedgehog) gene during brain development and during neural tube and somite formation. Mice that lack a functional Shh gene display microcephaly and severe neural tube defects. Midbrain and forebrain fields are reduced, and optic vesicles fuse across the midline resulting in a cyclops structure. Thus, Shh has a profound function in brain development. In addition, Shh ablation leads to a loss of floor plate cells and sclerotomes along the anterior-posterior axis, indicating a requirement of Shh in the patterning of the neural tube and the somites. Animal models of human diseases. We have generated mouse models designed to aid in the process of testing novel avenues of therapy. (1) Cancer cells are eliminated by apoptosis in mice that overexpress wild-type p53, a tumor suppressor function. (2) Sphingolipid metabolism is characteristically affected in our mouse models of Sandhoff and Tay-Sachs genetic disorders. (3) Lack of insulin receptors in mice leads to metabolic derangements similar to insulin-dependent diabetes mellitus. (4) Functional ablation of the dopamine D3 receptor gene results in hyperactive mice that are potential targets for therapeutic intervention in corresponding human behavioral disorders.