MAMMALIAN DEVELOPMENTAL GENETICS AND ANIMAL MODELS OF HUMAN DISEASES

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The Section on Transgene Regulation works simultaneously on projects in the field of mouse developmental genetics and on mouse models of human diseases. Our developmental studies have addressed the function of two mouse LIM-homeobox genes, Lhx3 and Lhx4, in pituitary organogenesis. The onset of Lhx3 and Lhx4 expression coincides with the formation of Rathke's pouch, the primordium of the pituitary gland. Our studies of mouse embryos that lack the function of Lhx3, Lhx4, or both, have shown that the organ forms in a stepwise fashion. Both genes act redundantly during the formation of a definitive pouch. Thereafter, Lhx3 controls a critical step of pituitary fate commitment. Later, Lhx3 as well as Lhx4 regulate the proliferation and differentiation of pituitary-specific cell lineages. Thus, Lhx3 and Lhx4 dictate pituitary organ identity by controlling developmental decisions at multiple stages of organogenesis. The sonic hedgehog (Shh) gene plays a critical role in patterning of vertebrate embryonic tissues. We have continued our study of the Shh knockout embryo with an examination of Shh function during limb development and find that the gene is essential for the outgrowth of distal limb structures. In addition, the gene is required for anterior-posterior patterning of the limbs. We know this because grafts of Shh mutant mesenchyme are unable to induce patterning activity. The absence of Fgf4 and 5'Hox-d gene expression in Shh mutant limbs is consistent with the notion that Shh regulates limb patterning via these genes. Animal models have been developed for tumor suppression and for Hirschsprung's disease. (1) In the tumor suppression model, we examined lenses of transgenic mice that express different constellations of viral oncogenes and the tumor suppressors RB and p53. Tumor suppressors are able to control the action of viral oncogenes in this model. However, excess suppression can cause cell death. Our results encourage attempts to counteract the deleterious function of oncogenes by a combination of measures aimed at decreasing cell proliferation and enhancing cell apoptosis. (2) Our recent observations of mice that carry a null mutation in the gene encoding glial cell line derived neurotrophic factor (GDNF) have shed new light on the pathogenesis of Hirschsprung's disease. It appears that partial loss of enteric neurons is sufficient to cause life threatening dysfunction of gut peristalsis among our population of GDNF mutant mice.