Neural crest-directed gene transfer demonstrates Wnt1 role in melanocyte expansion and differentiation during mouse development

Wnt1 signaling has been implicated as one factor involved in neural crest-d erived melanocyte (NC-M) development. Mice deficient for both Wnt1 and Wnt3 a have a marked deficiency in trunk neural crest derivatives including NC-M s, We have used cell lineage-directed gene targeting of Wnt signaling genes to examine the effects of Wnt signaling in mouse neural crest development. Gene expression was directed to cell lineages by infection with subgroup A avian leukosis virus vectors in lines of transgenic mice that express the retrovirus receptor tv-a. Transgenic mice with tva in either nestin-express ing neural precursor cells (line Ntva) or dopachrome tautomerase (DCT)-expr essing melanoblasts (line DCTtva) were analyzed, We overstimulated Wnt sign aling in two ways: directed gene transfer of Wnt1 to Ntva(+) cells and tran sfer of beta-catenin to DCTtva(+) NC-M precursor cells, In both methods, NC -M expansion and differentiation were effected. Significant increases were observed in the number of NC-Ms [melanin(+) and tyrosinase-related protein 1 (TYRP1)(+) cells], the differentiation of melanin-TYRP1(+) cells to melan in(+) TYRP1(+) NC-Ms, and the intensity of pigmentation per NC-M. These dat a are consistent with Wnt1 signaling being involved in both expansion and d ifferentiation of migrating NC-Ms in the developing mouse embryo, The use o f lineage-directed gene targeting will allow the dissection of signaling mo lecules involved in NC development and is adaptable to other mammalian deve lopmental systems.