Huntingtin-associated protein 1 (Hap1) mutant mice bypassing the early postnatal lethality are neuroanatomically normal and fertile but display growth retardation.
Huntingtin-associated protein 1 (Hap1) is the first huntingtin interacting protein identified in a yeast two-hybrid screen. Although Hap1 expression has been demonstrated in neuronal and non-neuronal tissues, its molecular role is poorly understood. Recently, it has been shown that targeted disruption of Hap1 in mice results in early postnatal death as a result of depressed feeding behavior. Although this result clearly demonstrates an essential role of Hap1 in postnatal feeding, the mechanisms leading to this deficiency, as well as the role of Hap1 in adults, remain unclear. Here we show that Hap1 null mutants display suckling defects and die within the first days after birth due to starvation. Upon reduction of the litter size, some mutants survive into adulthood and display growth retardation with no apparent brain or behavioral abnormalities, suggesting that Hap1 function is essential only for early postnatal feeding behavior. Using a conditional gene repair strategy, we also show that the early lethality can be rescued if Hap1 expression is restored in neuronal cells before birth. Furthermore, no synergism was observed between Hap1 and huntingtin mutation during mouse development. Our results demonstrate that Hap1 has a fundamental role in regulating postnatal feeding in the first 2 weeks after birth and a non-essential role in the adult mouse.
Dragatsis
Ioannis
I
Department of Physiology, College of Medicine, The University of Tennessee, Health Science Center, Memphis, TN 38163, USA. idragatsis@utmem.edu
Zeitlin
Scott
S
Dietrich
Paula
P
D000367:Age Factors; D000818:Animals; D001835:Body Weight / Q000235:genetics; D018390:Gene Targeting; D006720:Homozygote; D000071058:Huntingtin Protein; D017403:In Situ Hybridization; D051379:Mice / Q000235:genetics* / Q000254:growth & development*; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009420:Nervous System / Q000033:anatomy & histology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism
C490758:Hap1 protein, mouse; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins