Human Molecular Genetics, 2002, Vol. 11, No. 8 945-959
© 2002 Oxford University Press
Targeted disruption of Huntingtin-associated protein-1 (Hap1) results in postnatal death due to depressed feeding behavior
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1Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, Children's and Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada 2Medical Genetics Section, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK 3Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA 4Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada and 5Laboratory of Molecular Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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.
* To whom correspondence should be addressed at: Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia Vancouver, British Columbia V5H 4H4, Canada. Tel: 604-875-3535; Fax: 604-875-3819; Email: mrh{at}cmmt.ubc.ca
The authors wish it to be known that in their opinion, the first three authors should be regarded as joint First Authors.
Present Address: Section of Genetics and Informatics, University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, UK
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