THE FORKHEAD WINGED HELIX GENE MF1 IS DISRUPTED IN THE PLEIOTROPIC MOUSE MUTATION CONGENITAL HYDROCEPHALUS/

Mf1 encodes a forkhead/winged helix transcription factor expressed in many embryonic tissues, including prechondrogenic mesenchyme, periocul ar mesenchyme, meninges, endothelial cells, and kidney. Homozygous nul l Mf1(lacZ) mice die at birth with hydrocephalus, eye defects, and mul tiple skeletal abnormalities identical to those of the classical mutan t, congenital hydrocephalus. We show that congenital hydrocephalos inv olves a point mutation in Mf1, generating a truncated protein lacking the DNA-binding domain. Mesenchyme cells from Mf1(lacZ) embryos differ entiate poorly into cartilage in micromass culture and do not respond to added BMP2 and TGF beta 1. The differentiation of arachnoid cells i n the mutant meninges is also abnormal. The human Mf1 homolog FREAC3 i s a candidate gene for ocular dysgenesis and glaucoma mapping to chrom osome 6p25-pter, and deletions of this region are associated with mult iple developmental disorders, including hydrocephaly and eye defects.