The genes of the achaete-scute complex (AS-C) of drosophila, which encode transcription regulators of the helix-loop-helix (HLH) type, control the development of neural precursors in the peripheral and central nervous system (CNS). The activity of these positive regulators of neurogenesis is antagonized, among others, by the genes of theEnhancer of Split complex (Espl) and hairy (h), which also encode HLH factors. These factors could act either by repressing transcription of the AS-C genes, or by blocking AS-C factor activity through heterodimerization, or by repressing the target genes activated by AS-C.Mash1 is a mouse homolog of the drosophila AS-C genes, and we have shown that its function is necessary for the differentiation of olfactory and sympathetic neurons (GUILLEMOT et al (1993) Cell, 75, 463-476). The Hes genes are homologous to the Espl and h genes, and at least two of them, Hes1 andHes5 , are expressed by precursors of the CNS (AKAZAWA et al. (1992) J. Biol. Chem., 267, 21879-21885; SASAI et al. (1992) Genes Dev., 6, 2620-2634). We have generated mutations in these genes by homologous recombination in embryonic stem cells. Hes 1 -/- embryos display, in addition to a lack of mesoderm with a low penetrance, a failure of closure of the anterior neural tube. Analysis of Hes5 mutant mice is in progress. The phenotype of these mutations and the study of the interactions betweenHes1, Hes5 and Mash1 will be reported.