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

被引:40
作者
Dietrich, Paula [1 ]
Shanmugasundaram, Revathi [1 ]
E, Shuyu [1 ]
Dragatsis, Ioannis [1 ]
机构
[1] Univ Tennessee, Ctr Hlth Sci, Dept Physiol, Memphis, TN 38163 USA
关键词
CEREBROSPINAL-FLUID; DISEASE GENE; CHOROID-PLEXUS; TARGETED DISRUPTION; EMBRYONIC LETHALITY; TRANSCRIPTION; EXPRESSION; BRAIN; INACTIVATION; DIFFERENTIATION;
D O I
10.1093/hmg/ddn324
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (Hdh) gene 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 cerebral spinal fluid (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.
引用
收藏
页码:142 / 150
页数:9
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