Analysis of the role of basic-helix-loop-helix transcription factors in the development of neural lineages in the mouse.

The development of neural lineages is a complex process which is being actively investigated in both vertebrate and invertebrate models. A detailed genetic analysis of sensory organ development in Drosophila has revealed the contribution of numerous genes which function to progressively to specify the fate of neural precursor cells. Many of these genes have mammalian homologs which are also expressed in the developing nervous system, among which two families of genes encoding transcription factors of the helix-loop-helix class. The two mouse Mash genes are homologs of the Drosophila achaete-scute genes, which are positive regulators of neural precursor development. The five mouse HES genes are homologs of the Drosophila hairy and Enhancer of split genes, which act as negative regulators in this process. We have generated a null mutation in the mouse Mash1 gene by homologous recombination in embryonic stem cells. Animals homozygous for this mutation die at birth, and show severe losses in olfactory and autonomic neurons. In both lineages, the mutation appears to affect the development of neuronal precursors. We have also started a genetic analysis of the mouse HES genes to study their function during neurogenesis and the possibility that they regulate the activity of Mash1 and other positive regulators.