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.

[1]  C. Lagenaur,et al.  An L1-like molecule, the 8D9 antigen, is a potent substrate for neurite extension. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Christopher A Ross,et al.  Widespread expression of Huntington's disease gene (IT15) protein product , 1995, Neuron.

[3]  J. Trowsdale,et al.  Disassembly of nuclear inclusions in the dividing cell--a novel insight into neurodegeneration. , 1999, Human molecular genetics.

[4]  David J. Anderson,et al.  Subregion- and Cell Type–Restricted Gene Knockout in Mouse Brain , 1996, Cell.

[5]  N. Henderson,et al.  Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[6]  L. Raymond,et al.  Life Without Huntingtin , 1999, Journal of neurochemistry.

[7]  F. Walsh,et al.  Neurite outgrowth in response to transfected N-CAM changes during development and is modulated by polysialic acid , 1990, Neuron.

[8]  S. W. Davies,et al.  Formation of polyglutamine inclusions in non-CNS tissue. , 1999, Human molecular genetics.

[9]  A. Hackam,et al.  Wild-Type Huntingtin Protects from Apoptosis Upstream of Caspase-3 , 2000, The Journal of Neuroscience.

[10]  S. Folstein,et al.  Huntington's disease gene (IT15) is widely expressed in human and rat tissues , 1993, Neuron.

[11]  William Slikker,et al.  Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration , 1997, Brain Research.

[12]  D. Tagle,et al.  Recent advances in understanding the pathogenesis of Huntington's disease , 1999, Trends in Neurosciences.

[13]  Jacqueline K. White,et al.  Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion , 1997, Nature Genetics.

[14]  R. Albin,et al.  Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues , 1993, Nature Genetics.

[15]  S. W. Davies,et al.  Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. , 1997, Science.

[16]  M. Colombel,et al.  Hyperplasia and apoptosis. Opposing cellular processes that regulate the response of the rabbit bladder to transient outlet obstruction. , 1994, Laboratory investigation; a journal of technical methods and pathology.

[17]  S. W. Davies,et al.  Exon 1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice , 1996, Cell.

[18]  J. Roder,et al.  Heterophilic Binding of L1 on Unmyelinated Sensory Axons Mediates Schwann Cell Adhesion and Is Required for Axonal Survival , 1999, The Journal of cell biology.

[19]  R. Hynes,et al.  Contact and adhesive specificities in the associations, migrations, and targeting of cells and axons , 1992, Cell.

[20]  M. MacDonald,et al.  Heterogeneous Topographic and Cellular Distribution of Huntingtin Expression in the Normal Human Neostriatum , 1997, The Journal of Neuroscience.

[21]  R. Carraway,et al.  Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons , 1995, Neuron.

[22]  R. Vallee,et al.  Fast transport and retrograde movement of huntingtin and HAP 1 in axons , 1997, Neuroreport.

[23]  S. Zeitlin,et al.  Expression of the Huntingtin-associated protein 1 gene in the developing and adult mouse , 2000, Neuroscience Letters.

[24]  J. Penney,et al.  Axonal transport of N-terminal huntingtin suggests early pathology of corticostriatal projections in Huntington disease. , 1999, Journal of neuropathology and experimental neurology.

[25]  Y. Bordelon,et al.  Early effects of intrastriatal injections of quinolinic acid on microtubule-associated protein-2 and neuropeptides in rat basal ganglia , 1999, Neuroscience.

[26]  Virginia E. Papaioannou,et al.  Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue , 1995, Nature Genetics.

[27]  A. Parent,et al.  Neuronal degeneration in the basal ganglia and loss of pallido-subthalamic synapses in mice with targeted disruption of the Huntington's disease gene , 1999, Brain Research.

[28]  A. Joyner,et al.  Inactivation of the mouse Huntington's disease gene homolog Hdh. , 1995, Science.

[29]  Carlos Cepeda,et al.  Enhanced sensitivity to N‐methyl‐D‐aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease , 1999, Journal of neuroscience research.

[30]  S. Floresco,et al.  Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes , 1995, Cell.

[31]  S. Zeitlin,et al.  Mouse mutant embryos lacking huntingtin are rescued from lethality by wild-type extraembryonic tissues. , 1998, Development.

[32]  Jian Wang,et al.  CaMKII regulates the frequency-response function of hippocampal synapses for the production of both LTD and LTP , 1995, Cell.

[33]  S. Hersch,et al.  Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[34]  L. Landmesser,et al.  Distinct roles for adhesion molecules during innervation of embryonic chick muscle. , 1988, Developmental biology.

[35]  J. Crawley.  Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests 1 Published on the World Wide Web on 2 December 1998. 1 , 1999, Brain Research.

[36]  E. Wagner,et al.  A strain‐independent postnatal neurodegeneration in mice lacking the EGF receptor , 1998, The EMBO journal.

[37]  M. MacDonald,et al.  Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice. , 2000, Human molecular genetics.

[38]  M. MacDonald,et al.  Huntington's disease: translating a CAG repeat into a pathogenic mechanism , 1996, Current Opinion in Neurobiology.

[39]  H. Kimura,et al.  In VivoHypoxia-Induced Neuronal Damage with an Enhancement of Neuronal Nitric Oxide Synthase Immunoreactivity in Hippocampus , 1997, Experimental Neurology.

[40]  H. Lehrach,et al.  SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates. , 1998, Molecular cell.

[41]  M. MacDonald,et al.  Normal and Expanded Huntington’s Disease Gene Alleles Produce Distinguishable Proteins Due to Translation Across the CAG Repeat , 1995, Molecular medicine.

[42]  D. Rubinsztein,et al.  A molecular investigation of true dominance in Huntington’s disease , 1999, Journal of medical genetics.

[43]  C. Schwarz,et al.  Wild-Type and Mutant Huntingtins Function in Vesicle Trafficking in the Secretory and Endocytic Pathways , 1998, Experimental Neurology.

[44]  S. Zeitlin,et al.  CaMKIIα‐cre transgene expression and recombination patterns in the mouse brain , 2000 .