MOUSE MUTANT EMBRYOS LACKING HUNTINGTIN ARE RESCUED FROM LETHALITY BYWILD-TYPE EXTRAEMBRYONIC TISSUES

Mouse embryos nullizygous for a targeted disruption of the Huntington' s disease gene homologue (Hdh), which encodes a protein (huntingtin) o f unknown biochemical function, become developmentally retarded and di sorganized, and die early in development. Using chimeric analysis, we demonstrate that extensively chimeric embryos derived by injection of Hdh null ES cells into wildtype host blastocysts are rescued from leth ality. In contrast, when wild-type ES cells are injected into Hdh null blastocysts, the chimeric embryos are morphologically indistinguishab le from Hdh null mutants derived from natural matings, and die shortly after gastrulation. Therefore, the primary defect in the absence of h untingtin lies in extraembryonic tissues, whereas the epiblast and its derivatives are affected secondarily. It is likely that the mutation results in impairment of the nutritive functions of the visceral endod erm, which otherwise appears to differentiate normally, as evidenced b y the expression of several specific marker genes. Consistent with pre liminary histochemical analysis indicating that at least the transport of ferric ions is defective in Hdh mutants and in conjunction with th e known localization of huntingtin in the membranes of vesicles associ ated with microtubules, we hypothesize that this protein is involved i n the intracellular trafficking of nutrients in early embryos.