Human Molecular Genetics Advance Access originally published online on October 20, 2004
Human Molecular Genetics 2004 13(24):3115-3125; doi:10.1093/hmg/ddh328
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Human Molecular Genetics, Vol. 13, No. 24 © Oxford University Press 2004; all rights reserved
Huntingtin-associated protein 1 (Hap1) mutant mice bypassing the early postnatal lethality are neuroanatomically normal and fertile but display growth retardation
1Department of Physiology, College of Medicine, The University of Tennessee, Health Science Center, Memphis, TN 38163, USA and 2Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
Received August 2, 2004; Accepted October 11, 2004
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.
* To whom correspondence should be addressed at: Department of Physiology, The University of Tennessee, Health Science Center, 894 Union Avenue, Room 502, Nash Building, Memphis, TN 38163, USA. Tel: +1 9014483615; Fax: +1 9014487126; Email: idragatsis{at}utmem.edu
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