Targeted disruption of Huntingtin-associated protein-1 (Hap1) results in postnatal death due to depressed feeding behavior

Edmond Y W Chan, Jamal Nasir, Claire-Anne Gutekunst, Sarah Coleman, Alan Maclean, Alex Maas, Martina Metzler, Marina Gertsenstein, Christopher A Ross, Andràs Nagy, Michael R Hayden

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63 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)945-959
Number of pages15
JournalHuman Molecular Genetics
Volume11
Issue number8
DOIs
Publication statusPublished - 15 Apr 2002

Keywords

  • animal nutritional physiological phenomena
  • animals
  • animals, suckling
  • body constitution
  • eating
  • homozygote
  • hypothalamus
  • leptin
  • mice
  • microtubule-associated proteins
  • mutagenesis, site-directed
  • nerve tissue proteins
  • neurons
  • nuclear proteins
  • starvation

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    Chan, E. Y. W., Nasir, J., Gutekunst, C-A., Coleman, S., Maclean, A., Maas, A., ... Hayden, M. R. (2002). Targeted disruption of Huntingtin-associated protein-1 (Hap1) results in postnatal death due to depressed feeding behavior. Human Molecular Genetics , 11(8), 945-959. https://doi.org/10.1093/hmg/11.8.945