Loss of Usp9x disrupts cortical architecture, hippocampal development and TGFβ-mediated axonogenesis

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dc.contributor.authorStegeman, S.
dc.contributor.authorJolly, L.
dc.contributor.authorPremarathne, S.
dc.contributor.authorGecz, J.
dc.contributor.authorRichards, L.
dc.contributor.authorMackay-Sim, A.
dc.contributor.authorWood, S.
dc.contributor.editorAlsina, B.
dc.date.issued2013
dc.descriptionExtent: 12 p.
dc.description.abstractThe deubiquitylating enzyme Usp9x is highly expressed in the developing mouse brain, and increased Usp9x expression enhances the self-renewal of neural progenitors in vitro. USP9X is a candidate gene for human neurodevelopmental disorders, including lissencephaly, epilepsy and X-linked intellectual disability. To determine if Usp9x is critical to mammalian brain development we conditionally deleted the gene from neural progenitors, and their subsequent progeny. Mating Usp9xloxP/loxP mice with mice expressing Cre recombinase from the Nestin promoter deleted Usp9x throughout the entire brain, and resulted in early postnatal lethality. Although the overall brain architecture was intact, loss of Usp9x disrupted the cellular organization of the ventricular and sub-ventricular zones, and cortical plate. Usp9x absence also led to dramatic reductions in axonal length, in vivo and in vitro, which could in part be explained by a failure in Tgf-β signaling. Deletion of Usp9x from the dorsal telencephalon only, by mating with Emx1-cre mice, was compatible with survival to adulthood but resulted in reduction or loss of the corpus callosum, a dramatic decrease in hippocampal size, and disorganization of the hippocampal CA3 region. This latter phenotypic aspect resembled that observed in Doublecortin knock-out mice, which is an Usp9x interacting protein. This study establishes that Usp9x is critical for several aspects of CNS development, and suggests that its regulation of Tgf-β signaling extends to neurons.
dc.description.statementofresponsibilityShane Stegeman, Lachlan A. Jolly, Susitha Premarathne, Jozef Gecz, Linda J. Richards, Alan Mackay-Sim and Stephen A. Wood
dc.identifier.citationPLoS One, 2013; 8(7):1-12
dc.identifier.doi10.1371/journal.pone.0068287
dc.identifier.issn1932-6203
dc.identifier.issn1932-6203
dc.identifier.orcidJolly, L. [0000-0003-4538-2658]
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]
dc.identifier.urihttp://hdl.handle.net/2440/79636
dc.language.isoen
dc.publisherPublic Library of Science
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1009248
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/628952
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/250340
dc.rightsCopyright: © 2013 Stegeman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.source.urihttps://doi.org/10.1371/journal.pone.0068287
dc.subjectCentral Nervous System
dc.subjectCerebellar Cortex
dc.subjectHippocampus
dc.subjectAstrocytes
dc.subjectNeurons
dc.subjectAxons
dc.subjectAnimals
dc.subjectMice, Knockout
dc.subjectMice
dc.subjectUbiquitin Thiolesterase
dc.subjectEndopeptidases
dc.subjectTransforming Growth Factor beta
dc.subjectOrgan Size
dc.subjectSignal Transduction
dc.subjectGene Deletion
dc.subjectGenes, Lethal
dc.subjectFemale
dc.subjectMale
dc.subjectNeurogenesis
dc.subjectDoublecortin Protein
dc.titleLoss of Usp9x disrupts cortical architecture, hippocampal development and TGFβ-mediated axonogenesis
dc.title.alternativeLoss of Usp9x disrupts cortical architecture, hippocampal development and TGFbeta-mediated axonogenesis
dc.typeJournal article
pubs.publication-statusPublished

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