ANALYSIS OF THE VESTIGIAL TAIL MUTATION DEMONSTRATES THAT WNT-3A GENEDOSAGE REGULATES MOUSE AXIAL DEVELOPMENT

Mice homozygous for the recessive mutation vestigial tail (vt), which arose spontaneously on Chromosome 11, exhibit vertebral abnormalities, including loss of caudal vertebrae leading to shortening of the tail. Wnt-3a, a member of the wingless family of secreted glycoproteins, ma ps to the same chromosome. Embryos homozygous for a null mutation in W nt-3a (Wnt-3a(neo)) have a complete absence of tail bud development an d are truncated rostral to the hindlimbs. Several lines of evidence re veal that vt is a hypomorphic allele of Wnt-3a. We show that Wnt-3a an d vt cosegregate in a high-resolution backcross and fail to complement , suggesting that Wnt-3a(neo) and vt are allelic. Embryos heterozygous for both alleles have a phenotype intermediate between that of Wnt-3a (neo) and vt homozygotes, lacking a tail, but developing thoracic and a variable number of lumbar vertebrae. Although no gross alteration in the Wnt-3a gene was detected in vt mice and the Wnt-3a coding region was normal, Wnt-3a expression was markedly reduced in vt/vt embryos co nsistent with a regulatory mutation in Wnt-3a. Furthermore, the analys is of allelic combinations indicates that Wnt-3a is required throughou t the period of tail bud development for caudal somitogenesis. Interes tingly, increasing levels of Wnt-3a activity appear to be necessary fo r the formation of more posterior derivatives of the paraxial mesoderm .