TY - JOUR
T1 - Targeted disruption of Huntingtin-associated protein-1 (Hap1) results in postnatal death due to depressed feeding behavior
AU - Chan, Edmond Y.W.
AU - Nasir, Jamal
AU - Gutekunst, Claire Anne
AU - Coleman, Sarah
AU - Maclean, Alan
AU - Maas, Alex
AU - Metzler, Martina
AU - Gertsenstein, Marina
AU - Ross, Christopher A.
AU - Nagy, Andràs
AU - Hayden, Michael R.
N1 - Funding Information:
E.Y.W.C. is supported by fellowships from the Canadian Institutes for Health Research and Michael Smith Foundation for Health Research. J.N. was the recipient of a MRC (UK) Career Development Award and a Huntington Society of Canada NAVIGATOR research award. C-.A.G. is supported by a grant from the National Science Foundation (IBN-9983078. M.R.H. is a holder of a Canada Research Chair. This work has been supported by the Canadian Institutes for Health Research (to M.R.H.), Canadian Genetic Diseases Network (to M.R.H.) and the Scottish Hospital Endowments Research Trust (SHERT) (to J.N.).
PY - 2002/4/15
Y1 - 2002/4/15
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/11.8.945
DO - 10.1093/hmg/11.8.945
M3 - Article
C2 - 11971876
AN - SCOPUS:0037091010
SN - 0964-6906
VL - 11
SP - 945
EP - 959
JO - Human molecular genetics
JF - Human molecular genetics
IS - 8
ER -