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

Dietrich, Paula; Shanmugasundaram, R.; Shuyu, E; Dragatsis, Ioannis

doi:10.1093/hmg/ddn324

Cited by 51 publications

(46 citation statements)

References 68 publications

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“…On the other hand, HTT gene knockout in the mouse results in embryonic lethality [2–4], and reduced levels lead to developmental brain defects and perinatal lethality [48]. In addition, lack of HTT in the adult mammalian brain has adverse effects [20, 49]. This suggests that a certain level of wild-type HTT is required for appropriate brain function, making allele-selective approaches highly attractive.…”

Section: Discussionmentioning

confidence: 99%

Replacement of huntingtin exon 1 by trans-splicing

Rindt

Yen

Thebeau

et al. 2012

Cell. Mol. Life Sci.

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Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansion in the amino-terminus of huntingtin (HTT). HD offers unique opportunities for promising RNA-based therapeutic approaches aimed at reducing mutant HTT expression, since the HD mutation is considered to be a “gain-of-function” mutation. Allele-specific strategies that preserve expression from the wild-type allele and reduce the levels of mutant protein would be of particular interest. Here, we have conducted proof-of-concept studies to demonstrate that spliceosome-mediated trans-splicing is a viable molecular strategy to specifically repair the HTT allele. We employed a dual plasmid transfection system consisting of a pre-mRNA trans-splicing module (PTM) containing HTT exon 1 and a HTT minigene to demonstrate that HTT exon 1 can be replaced in trans. We detected the presence of the trans-spliced RNA in which PTM exon 1 was correctly joined to minigene exons 2 and 3. Furthermore, exon 1 from the PTM was trans-spliced to the endogenous HTT pre-mRNA in cultured cells as well as disease-relevant models, including HD patient fibroblasts and primary neurons from a previously described HD mouse model. These results suggest that the repeat expansion of HTT can be repaired successfully not only in the context of synthetic minigenes but also within the context of HD neurons. Therefore, pre-mRNA trans-splicing may be a promising approach for the treatment of HD and other dominant genetic disorders.

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Section: Discussionmentioning

confidence: 99%

Replacement of huntingtin exon 1 by trans-splicing

Rindt

Yen

Thebeau

et al. 2012

Cell. Mol. Life Sci.

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“…16 and Figure 4A). The phenotype was linked to abnormalities of the CP and of the subcommissural organ (SCO), with stenosis of the Sylvius aqueduct that links the third and the fourth ventricles.…”

Section: Inactivation Of the Htt Gene In Wnt-1 Cell Lineage Alters Pcmentioning

confidence: 90%

“…Altered CSF production from the CP (14) or defects in ependymal flow as a result of dysmotile cilia (15) result in aqueduct stenosis and hydrocephalus. In mice, specific deletion of Htt in the Wnt-1 lineage results in congenital hydrocephalus, which suggests that Htt could play a role in the regulation of CSF homeostasis (16).…”

Section: Introductionmentioning

confidence: 99%

Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease

Keryer¹,

Pineda²,

Liot³

et al. 2011

J. Clin. Invest.

126

130

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IntroductionHuntington disease (HD) is an autosomal-dominant neurodegenerative disorder caused by the pathogenic expansion of the polyglutamine (polyQ) N-terminal stretch in the huntingtin protein (HTT; encoded by HTT). HD is characterized by the dysfunction and death of neurons in the brain, leading to devastating cognitive, psychiatric, and motor symptoms in patients. Studies in multiple cell and animal model systems support the notion that polyQ expansion in mutant Htt leads to the gain of new toxic functions and loss of the neuroprotective functions of the WT Htt (1).Although some of its functions are linked to transcriptional activities in health and disease, Htt is primarily a cytoplasmic protein that associates with microtubules (MTs) and vesicles. Htt regulates intracellular trafficking of various organelles, including vesicles, by interacting with the dynein/dynactin pathway (2-4). Htt facilitates MT-dependent transport by interacting directly with dynein (2) and indirectly via huntingtin-associated protein 1 (HAP1), which binds to the dynactin p150 Glued subunit (3,(5)(6)(7). In pathological situations, the Htt-HAP1-dynactin complex is altered, resulting in a reduction of vesicular transport in neurons (3). These findings show that Htt integrates vesicular transport by regulating the activity of specific protein complexes containing the dynein/dynactin and kinesin 1 complexes and adaptor proteins such as HAP1.With 2 patterns of axonemal MTs (9 + 0 in primary cilia and 9 + 2 in motile cilia), cilia are involved in sensory role, motility, and flow generation. Within the last 5 years, the importance of this

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“…Reissner's fibre extends from the SCO through the fourth ventricle to the end of the spinal cord central canal, maintaining the patency of the Sylvian aqueduct and so allowing CSF to flow through this bottleneck and into the fourth ventricle . Importantly, there are many examples of mice in which gene loss (Blackshear et al, 2003;Dietrich et al, 2009), or the over expression of transgenes (Lee et al, 2012;Louvi and Wassef, 2000), is accompanied by deficient SCO formation or Reissner's fibre production and hydrocephalus, implying that abnormal development of this structure plays a central role in aqueductal stenosis.…”

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confidence: 99%

Expansion of the lateral ventricles and ependymal deficits underlie the hydrocephalus evident in mice lacking the transcription factor NFIX

et al. 2015

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Nuclear factor one X (NFIX) has been shown to play a pivotal role during the development of many regions of the brain, including the neocortex, the hippocampus and the cerebellum. Mechanistically, NFIX has been shown to promote neural stem cell differentiation through the activation of astrocyte-specific genes and via the repression of genes central to progenitor cell self-renewal. Interestingly, mice lacking Nfix also exhibit other phenotypes with respect to development of the central nervous system, and whose underlying causes have yet to be determined. Here we examine one of the phenotypes displayed by Nfix(-/-) mice, namely hydrocephalus. Through the examination of embryonic and postnatal Nfix(-/-) mice we reveal that hydrocephalus is first seen at around postnatal day (P) 10 in mice lacking Nfix, and is fully penetrant by P20. Furthermore, we examined the subcommissural organ (SCO), the Sylvian aqueduct and the ependymal layer of the lateral ventricles, regions that when malformed and functionally perturbed have previously been implicated in the development of hydrocephalus. SOX3 is a factor known to regulate SCO development. Although we revealed that NFIX could repress Sox3-promoter-driven transcriptional activity in vitro, SOX3 expression within the SCO was normal within Nfix(-/-) mice, and Nfix mutant mice showed no abnormalities in the structure or function of the SCO. Moreover, these mutant mice exhibited no overt blockage of the Sylvian aqueduct. However, the ependymal layer of the lateral ventricles was frequently absent in Nfix(-/-) mice, suggesting that this phenotype may underlie the development of hydrocephalus within these knockout mice.

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

Cited by 51 publications

References 68 publications

Replacement of huntingtin exon 1 by trans-splicing

Replacement of huntingtin exon 1 by trans-splicing

Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease

Expansion of the lateral ventricles and ependymal deficits underlie the hydrocephalus evident in mice lacking the transcription factor NFIX

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