title: Neurons lacking huntingtin differentially colonize brain and survive in chimeric mice.
abstract: To determine whether neurons lacking huntingtin can participate in development and survive in postnatal brain, we used two approaches in an effort to create mice consisting of wild-type cells and cells without huntingtin. In one approach, chimeras were created by aggregating the 4-8 cell embryos from matings of Hdh (+/-) mice with wild-type 4-8 cell embryos. No chimeric offspring that possessed homozygous Hdh (-/-) cells were obtained thereby, although statistical considerations suggest that such chimeras should have been created. By contrast, Hdh (-/-) ES cells injected into blastocysts yielded offspring that were born and in adulthood were found to have Hdh (-/-) neurons throughout brain. The Hdh (-/-) cells were, however, 5-10 times more common in hypothalamus, midbrain, and hindbrain than in telencephalon and thalamus. Chimeric animals tended to be smaller than wild-type littermates, and chimeric mice rich in Hdh (-/-) cells tended to show motor abnormalities. Nonetheless, no brain malformations or pathologies were evident. The apparent failure of aggregation chimeras possessing Hdh (-/-) cells to survive to birth is likely attributable to the previously demonstrated critical role of huntingtin in extraembryonic membranes. That Hdh (-/-) cells in chimeric mice created by blastocyst injection are under-represented in adult telencephalon and thalamus implies a role for huntingtin in the development of these regions, whereas the neurological dysfunction in brains enriched in Hdh (-/-) cells suggests a role for huntingtin in adult brain. Nonetheless, the lengthy survival of Hdh (-/-) cells in adult chimeric mice indicates that individual neurons in many brain regions do not require huntingtin to participate in normal brain development and to survive.
authors.affiliation: Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee, The Health Science Center, Memphis, Tennessee 38163, USA. areiner@utmem.edu
authors.forename: A
authors.initials: A
authors.lastname: Reiner
authors.forename: N
authors.initials: N
authors.lastname: Del Mar
authors.forename: C A
authors.initials: CA
authors.lastname: Meade
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.forename: I
authors.initials: I
authors.lastname: Dragatsis
authors.forename: S
authors.initials: S
authors.lastname: Zeitlin
authors.forename: D
authors.initials: D
authors.lastname: Goldowitz
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D002465:Cell Movement; D002470:Cell Survival; D002678:Chimera / Q000235:genetics*; D017930:Genes, Reporter; D005838:Genotype; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D009422:Nervous System Diseases / Q000175:diagnosis / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D012249:Rhombencephalon / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells; D015996:Survival Rate; D013687:Telencephalon / Q000378:metabolism / Q000473:pathology; D013788:Thalamus / Q000378:metabolism / Q000473:pathology
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins