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Human Molecular Genetics Advance Access published online on October 6, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn324
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Congenital hydrocephalus associated with abnormal subcommissural organ in mice lacking huntingtin in Wnt1 cell lineages

Paula Dietrich, Revathi Shanmugasundaram, E. Shuyu and Ioannis Dragatsis*

Department of Physiology, The University of Tennessee, Health Science Center, Memphis, TN 38163.

* Corresponding Author: Ioannis Dragatsis, Ph.D. Department of Physiology The University of Tennessee Health Science Center 894 Union Avenue, room 502 Nash BLDG Memphis, TN 38163 Phone: (901) 448-3615 Fax: (901) 448-7126 Email: idragatsis{at}utmem.edu

Received July 19, 2008; Revised October 3, 2008; Accepted October 3, 2008

Huntingtin (htt) is a 350 kDa protein of unknown function, with no homologies with other known proteins. Expansion of a polyglutamine stretch at the N-terminus of htt causes Huntington's disease (HD), a dominant neurodegenerative disorder. Although it is generally accepted that HD is caused primarily by a gain-of-function mechanism, recent studies suggest that loss-of-function may also be part of HD pathogenesis. Huntingtin is an essential protein in the mouse since inactivation of the mouse HD homolog gene (Hdh) results in early embryonic lethality. Huntingtin is widely expressed in embryogenesis, and associated with a number of interacting proteins suggesting that htt may be involved in several processes including morphogenesis, neurogenesis and neuronal survival. To further investigate the role of htt in these processes, we have inactivated the Hdh gene in Wnt1 cell lineages using the Cre-loxP system of recombination. Here we show that conditional inactivation of the Hdh gene in Wnt1 cell lineages results in congenital hydrocephalus, implicating huntingtin for the first time in the regulation of CSF homeostasis. Our results show that hydrocephalus in mice lacking htt in Wnt1 cell lineages is associated with increase in CSF production by the choroid plexus, and abnormal subcommissural organ.


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