Mouse mutant embryos lacking huntingtin are rescued from lethality by wild-type extraembryonic tissues.
Mouse embryos nullizygous for a targeted disruption of the Huntington's disease gene homologue (Hdh), which encodes a protein (huntingtin) of unknown biochemical function, become developmentally retarded and disorganized, and die early in development. Using chimeric analysis, we demonstrate that extensively chimeric embryos derived by injection of Hdh null ES cells into wild-type host blastocysts are rescued from lethality. In contrast, when wild-type ES cells are injected into Hdh null blastocysts, the chimeric embryos are morphologically indistinguishable from Hdh null mutants derived from natural matings, and die shortly after gastrulation. Therefore, the primary defect in the absence of huntingtin 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 endoderm, which otherwise appears to differentiate normally, as evidenced by the expression of several specific marker genes. Consistent with preliminary histochemical analysis indicating that at least the transport of ferric ions is defective in Hdh mutants and in conjunction with the known localization of huntingtin in the membranes of vesicles associated with microtubules, we hypothesize that this protein is involved in the intracellular trafficking of nutrients in early embryos.
Dragatsis
I
I
Department of Genetics, Columbia University, New York, NY 10032, USA.
Efstratiadis
A
A
Zeitlin
S
S
D000818:Animals; D001755:Blastocyst / Q000502:physiology; D002678:Chimera; D003433:Crosses, Genetic; D017931:DNA Primers; D004622:Embryo, Mammalian / Q000502:physiology*; D005314:Embryonic and Fetal Development / Q000235:genetics*; D004707:Endoderm / Q000502:physiology; D005260:Female; D005313:Fetal Death; D018507:Gene Expression Regulation, Developmental; D005819:Genetic Markers; D006579:Heterozygote; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000096:biosynthesis; D001616:beta-Galactosidase / Q000096:biosynthesis
D017931:DNA Primers; D005819:Genetic Markers; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D001616:beta-Galactosidase