Molecular Neurobiology

, Volume 28, Issue 3, pp 259–275 | Cite as

Wild-type huntingtin plays a role in brain development and neuronal survival

  • Anton Reiner
  • Ioannis Dragatsis
  • Scott Zeitlin
  • Daniel Goldowitz
Article

Abstract

While the role of the mutated Huntington’s disease (HD) protein in the pathogenesis of HD has been the focus of intensive investigation, the normal protein has received less attention. Nonetheless, the wild-type HD protein appears to be essential for embryogenesis, since deletion of the HD gene in mice results in early embryonic lethality. This early lethality is due to a critical role the HD protein, called huntingtin (Htt), plays in extraembryonic membrane function, presumably in vesicular transport of nutrients. Studies of mutant mice expressing low levels of Htt and of chimeric mice generated by blastocyst injection of Hdh-/- embryonic stem cells show that wild-type Htt plays an important role later in development as well, specifically in forebrain formation. Moreover, various lines of study suggest that normal Htt is also critical for survival of neurons in the adult forebrain.

The observation that Htt plays its key developmental and survival roles in those brain areas most affected in HD raises the possibility that a subtle loss of function on the part of the mutant protein or a sequestering of wild-type Htt by mutant Htt may contribute to HD pathogenesis. Regardless of whether this is so, the prosurvival role of Htt suggests that HD therapies that block production of both wild-type and mutant Htt may themselves be harmful.

Index Entries

Basal ganglia cortex development Huntington’s Disease HD gene colonization 

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Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  • Anton Reiner
    • 1
  • Ioannis Dragatsis
    • 2
  • Scott Zeitlin
    • 3
  • Daniel Goldowitz
    • 1
  1. 1.Department of Anatomy and NeurobiologyThe University of Tennessee, The Health Science CenterMemphis
  2. 2.Department of Physiology, College of MedicineThe University of Tennessee, The Health Science CenterMemphis
  3. 3.Department of NeuroscienceUniversity of Virginia School of MedicineCharlottesville

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