Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice


Inactivation of the mouse homologue of the Huntington disease gene (Hdh) results in early embryonic lethality. To investigate the normal function of Hdh in the adult and to evaluate current models for Huntington disease (HD), we have used the Cre/loxP site-specific recombination strategy to inactivate Hdh expression in the forebrain and testis, resulting in a progressive degenerative neuronal phenotype and sterility. On the basis of these results, we propose that huntingtin is required for neuronal function and survival in the brain and that a loss-of-function mechanism may contribute to HD pathogenesis.

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Figure 1: Cre/loxP–mediated inactivation of Hdh.
Figure 2: Inactivation of Hdh expression in mouse brain.
Figure 3: Abnormal limb-clasping and brain morphology in mutant mice.
Figure 4: Brain histology in L7ag13 and R1ag5 mutants.
Figure 5: Fluoro-jade staining in mutant brains.
Figure 6: Altered MAP2 immunostaining and gliosis in mutant brains.
Figure 7: Spermatogenesis is affected in mutant testis.

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We thank R.S. Fisher and P. Dietrich for histological examinations; M. Mendelsohn for blastocyst injections; K. Ratnam and T. Kolar for technical assistance; M. MacDonald, J. Goldman and T. Jessell for antibodies; A. Efstratiadis for helpful discussions and support; D. Wolgemuth and E.X. Wu for suggestions; and P. Dietrich, J.-P. Liu, A. Yamamoto and R. Hen for critical reading of the manuscript. We are grateful for the generous support provided to S.Z. and M.S.L. by the Hereditary Disease Foundation and the Hereditary Disease Foundation's Cure Huntington's Disease Initiative.

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Correspondence to Scott Zeitlin.

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Dragatsis, I., Levine, M. & Zeitlin, S. Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat Genet 26, 300–306 (2000).

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