GENE AND TRANSGENE REGULATION IN THE DEVELOPING MOUSE

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Murine LIM-homeobox (Lhx) genes. This family of developmental transcription factors regulates important steps of organogenesis. Lhx2 and Lhx7, a pair of closely related genes, are essential for pattern formation, particularly in the developing central nervous system (CNS). Knockout analyses of these two genes are in progress to address their combinatorial functions in the CNS and elsewhere in the developing embryo. Lhx3 and Lhx4, another closely related pair of genes, is responsible for the formation of the adenohypophysis, and also plays an essential role in motoneuron innervation along the spinal chord, a function currently being assessed via double loss-of-function analysis. LIM-binding proteins. We have isolated Ldb1, a novel factor that binds LIM motifs present in LIM-homeodomain and LMO proteins. In collaboration with the laboratory of Dr. Dawid , we have shown that the murine Ldb1 and its frog counterpart XLdb1 synergize with the LIM-homeobox gene 1 to induce early determinators of development and to form secondary axes when injected in frog embryos. Glial cell line-derived neurotrophic factor (GDNF) was isolated as a neurotrophic factor for midbrain dopaminergic neurons. In view of its neurotrophic activity on a wide range of neuronal populations in vitro and in vivo, GDNF is being considered as a potential therapeutic agent for neuronal disorders. During mammalian development, GDNF is expressed not only in the nervous system, but also very prominently in the metanephric kidney and in the gastrointestinal tract, suggesting possible functions during organogenesis. We have investigated the role of GDNF during development by generating a null mutation in the murine GDNF locus. Together with the laboratories of Drs. Hoffer, Saarma and Sariola we were able to demonstrate that mutant mice show kidney agenesis or dysgenesis and defective enteric innervation. GDNF induces ureter bud formation and branching during metanephros development. In addition, the factor is essential for proper innervation of the gastrointestinal tract.