title: Expansion of the lateral ventricles and ependymal deficits underlie the hydrocephalus evident in mice lacking the transcription factor NFIX.
abstract: 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.
authors.affiliation: The School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Diana
authors.initials: D
authors.lastname: Vidovic
authors.affiliation: The School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Lachlan
authors.initials: L
authors.lastname: Harris
authors.affiliation: The School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Tracey J
authors.initials: TJ
authors.lastname: Harvey
authors.affiliation: The School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Yee Hsieh
authors.initials: YH
authors.lastname: Evelyn Heng
authors.affiliation: The School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Smith
authors.affiliation: Department of Biochemistry, Programs in Neuroscience and Genetics, Genomics & Bioinformatics, Developmental Genomics Group, New York State Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, New York 14203, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Osinski
authors.affiliation: School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Hughes
authors.affiliation: School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Thomas
authors.affiliation: Department of Biochemistry, Programs in Neuroscience and Genetics, Genomics & Bioinformatics, Developmental Genomics Group, New York State Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, New York 14203, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Gronostajski
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Bailey
authors.affiliation: The School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address: m.piper@uq.edu.au.
authors.forename: Michael
authors.initials: M
authors.lastname: Piper
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D019295:Computational Biology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004805:Ependyma / Q000196:embryology / Q000254:growth & development / Q000473:pathology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006849:Hydrocephalus / Q000235:genetics / Q000473:pathology*; D020547:Lateral Ventricles / Q000196:embryology / Q000254:growth & development / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051839:NFI Transcription Factors / Q000172:deficiency* / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051839:NFI Transcription Factors; D009419:Nerve Tissue Proteins; C497650:Nfix protein, mouse; D055748:SOXB1 Transcription Factors; C527786:Sox3 protein, mouse
keywords: Hydrocephalus; Nuclear factor one X; Reissner׳s fibre; Subcommissural organ; Transcription factor