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The Journal of Neuroscience, October 1, 2001, 21(19):7608-7619

Neurons Lacking Huntingtin Differentially Colonize Brain and Survive in Chimeric Mice

Anton Reiner¹, Nobel Del Mar¹, Christopher A. Meade¹, Huaitao Yang¹, Ioannis Dragatsis², Scott Zeitlin³, and Daniel Goldowitz¹

¹ Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee, The Health Science Center, Memphis, Tennessee 38163, and Departments of ² Genetics and Development and ³ Pathology, Columbia University, New York, New York 10032

To determine whether neurons lacking huntingtin can participate in development and survive in postnatal brain, we used two approaches in an effort to create mice consisting of wild-type cells and cells without huntingtin. In one approach, chimeras were created by aggregating the 4-8 cell embryos from matings of Hdh ^+/ mice with wild-type 4-8 cell embryos. No chimeric offspring that possessed homozygous Hdh ^/ cells were obtained thereby, although statistical considerations suggest that such chimeras should have been created. By contrast, Hdh ^/ ES cells injected into blastocysts yielded offspring that were born and in adulthood were found to have Hdh ^/ neurons throughout brain. The Hdh ^/ cells were, however, 5-10 times more common in hypothalamus, midbrain, and hindbrain than in telencephalon and thalamus. Chimeric animals tended to be smaller than wild-type littermates, and chimeric mice rich in Hdh ^/ cells tended to show motor abnormalities. Nonetheless, no brain malformations or pathologies were evident.

The apparent failure of aggregation chimeras possessing Hdh ^/ cells to survive to birth is likely attributable to the previously demonstrated critical role of huntingtin in extraembryonic membranes. That Hdh ^/ cells in chimeric mice created by blastocyst injection are under-represented in adult telencephalon and thalamus implies a role for huntingtin in the development of these regions, whereas the neurological dysfunction in brains enriched in Hdh ^/ cells suggests a role for huntingtin in adult brain. Nonetheless, the lengthy survival of Hdh ^/ cells in adult chimeric mice indicates that individual neurons in many brain regions do not require huntingtin to participate in normal brain development and to survive.

Key words: basal ganglia; cortex; development; Huntington's disease; HD gene; colonization

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21197608-12$05.00/0

This article has been cited by other articles:

				J. M. Van Raamsdonk, W. T. Gibson, J. Pearson, Z. Murphy, G. Lu, B. R. Leavitt, and M. R. Hayden Body weight is modulated by levels of full-length Huntingtin Hum. Mol. Genet., May 1, 2006; 15(9): 1513 - 1523. [Abstract] [Full Text] [PDF]

				E. B.D. Clabough and S. O. Zeitlin Deletion of the triplet repeat encoding polyglutamine within the mouse Huntington's disease gene results in subtle behavioral/motor phenotypes in vivo and elevated levels of ATP with cellular senescence in vitro Hum. Mol. Genet., February 15, 2006; 15(4): 607 - 623. [Abstract] [Full Text] [PDF]

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