Chan Edmond Y W, Nasir Jamal, Gutekunst Claire-Anne, Coleman Sarah, Maclean Alan, Maas Alex, Metzler Martina, Gertsenstein Marina, Ross Christopher A, Nagy Andràs, Hayden Michael R
Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, Children's and Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
Hum Mol Genet. 2002 Apr 15;11(8):945-59. doi: 10.1093/hmg/11.8.945.
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.
亨廷顿相关蛋白1（HAP-1）是一种在大脑中富集的与亨廷顿蛋白相关的蛋白质。为了深入了解HAP-1的正常生理作用，研究人员构建了在Hap1基因座纯合缺失的小鼠。HAP-1表达的缺失并未改变其相互作用蛋白亨廷顿蛋白和动力蛋白轻链p150亚基的总体脑表达水平。新生的Hap1(-/-)动物以预期的孟德尔频率出现，这表明HAP-1在胚胎发育过程中并非必需。出生后，Hap1(-/-)幼崽的进食行为减少，最终导致营养不良、脱水和过早死亡。70%的Hap1(-/-)幼崽在出生后第二天（P2）后无法存活，100%的Hap1(-/-)幼崽在P9后无法存活。从P2到死亡，Hap1(-/-)幼崽摄入的乳汁量明显减少。存活到P8的Hap1(-/-)幼崽出现饥饿迹象，包括血清瘦素水平大幅下降、脑重量减轻和脑皮质萎缩。HAP-1在下丘脑中特别富集，而下丘脑在调节进食行为方面有充分的文献记载。我们的结果表明，HAP-1在调节出生后的进食中起重要作用。
