TARGETED DISRUPTION OF MAMMALIAN HAIRY AND ENHANCER OF SPLIT HOMOLOG-1 (HES-1) LEADS TO UP-REGULATION OF NEURAL HELIX-LOOP-HELIX FACTORS, PREMATURE NEUROGENESIS, AND SEVERE NEURAL-TUBE DEFECTS

Mammalian hairy and Enhancer of split homolog-1 (HES-1) encodes a heli x-loop-helix (HLH) factor that is thought to act as a negative regulat or of neurogenesis. To directly investigate the functions of HES-1 in mammalian embryogenesis, we performed a targeted disruption of the HES -1 locus. Mice homozygous for the mutation exhibited severe neurulatio n defects and died during gestation or just after birth. In the develo ping brain of HES-1-null embryos, expression of the neural differentia tion factor Mash-1 and other neural HLH Factors was up-regulated and p ostmitotic neurons appeared prematurely. These results suggest that HE S-I normally controls the proper timing of neurogenesis and regulates neural tube morphogenesis.