title: Targeted disruption of Huntingtin-associated protein-1 (Hap1) results in postnatal death due to depressed feeding behavior.
abstract: HAP-1 is a huntingtin-associated protein that is enriched in the brain. To gain insight into the normal physiological role of HAP-1, mice were generated with homozygous disruption at the Hap1 locus. Loss of HAP-1 expression did not alter the gross brain expression levels of its interacting partners, huntingtin and p150glued. Newborn Hap1(-/-) animals are observed at the expected Mendelian frequency suggesting a non-essential role of HAP-1 during embryogenesis. Postnatally, Hap1(-/-) pups show decreased feeding behavior that ultimately leads to malnutrition, dehydration and premature death. Seventy percent of Hap1(-/-) pups fail to survive past the second postnatal day (P2) and 100% of Hap1(-/-) pups fail to survive past P9. From P2 until death, Hap1(-/-) pups show markedly decreased amounts of ingested milk. Hap1(-/-) pups that survive to P8 show signs of starvation including greatly decreased serum leptin levels, decreased brain weight and atrophy of the brain cortical mantel. HAP-1 is particularly enriched in the hypothalamus, which is well documented to regulate feeding behavior. Our results demonstrate that HAP-1 plays an essential role in regulating postnatal feeding.
authors.affiliation: Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, Children's and Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Edmond Y W
authors.initials: EY
authors.lastname: Chan
authors.forename: Jamal
authors.initials: J
authors.lastname: Nasir
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Gutekunst
authors.forename: Sarah
authors.initials: S
authors.lastname: Coleman
authors.forename: Alan
authors.initials: A
authors.lastname: Maclean
authors.forename: Alex
authors.initials: A
authors.lastname: Maas
authors.forename: Martina
authors.initials: M
authors.lastname: Metzler
authors.forename: Marina
authors.initials: M
authors.lastname: Gertsenstein
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: Andràs
authors.initials: A
authors.lastname: Nagy
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D000833:Animals, Suckling; D001824:Body Constitution; D000072159:Dynactin Complex; D004435:Eating / Q000235:genetics / Q000502:physiology*; D006720:Homozygote; D000071058:Huntingtin Protein; D007031:Hypothalamus / Q000196:embryology / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D013217:Starvation / Q000235:genetics / Q000378:metabolism
chemical_list: D000072159:Dynactin Complex; C490758:Hap1 protein, mouse; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D020738:Leptin; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins