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Type: Journal article
Title: The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour and neuronal outgrowth
Author: Jolly, L.
Homan, C.
Jacob, R.
Barry, S.
Gecz, J.
Citation: Human Molecular Genetics, 2013; 22(23):4673-4687
Publisher: Oxford Univ Press
Issue Date: 2013
ISSN: 0964-6906
Statement of
Lachlan A. Jolly, Claire C. Homan, Reuben Jacob, Simon Barry and Jozef Gecz
Abstract: Loss-of-function mutations in UPF3B result in variable clinical presentations including intellectual disability (ID, syndromic and non-syndromic), autism, childhood onset schizophrenia and attention deficit hyperactivity disorder. UPF3B is a core member of the nonsense-mediatedmRNAdecay (NMD) pathway that functions to rapidly degrade transcripts with premature termination codons (PTCs). Traditionally identified in thousands of human diseases, PTCs were recently also found to be part of 'normal' genetic variation in human populations. Furthermore, many human transcripts have naturally occurring regulatory features compatible with 'endogenous'PTCsstrongly suggesting roles ofNMDbeyondPTCmRNAcontrol. In this study,weinvestigated the role of Upf3b andNMD in neural cells.Weprovide evidence that suggests Upf3b-dependentNMD(Upf3b-NMD) is regulated at multiple levels during development including regulation of expression and sub-cellular localization of Upf3b. Furthermore, complementary expression of Upf3b, Upf3a and Stau1 stratify the developing dorsal telencephalon, suggesting that alternativeNMD,andthe related Staufen1-mediatedmRNAdecay (SMD) pathways are differentially employed. A loss of Upf3b-NMD in neural progenitor cells (NPCs) resulted in the expansion of cell numbers at the expense of their differentiation. In primary hippocampal neurons, loss of Upf3b-NMD resulted in subtle neurite growth effects. Our data suggest that the cellular consequences of loss of Upf3b-NMD can be explained in-part by changes in expression of key NMD-feature containing transcripts, which are commonly deregulated also in patients with UPF3B mutations. Our research identifies novel pathological mechanisms of UPF3B mutations and at least partly explains the clinical phenotype of UPF3B patients.
Keywords: Brain; Neurons; Cells, Cultured; Animals; Mice, Transgenic; Humans; Mice; RNA-Binding Proteins; Autistic Disorder; Schizophrenia, Childhood; Signal Transduction; Cell Differentiation; Organ Specificity; Gene Expression Regulation, Developmental; Female; Neurogenesis; Neural Stem Cells; Intellectual Disability; Nonsense Mediated mRNA Decay
Description: HMG Advance Access published July 2, 2013
Rights: © The Author 2013.
RMID: 0020133063
DOI: 10.1093/hmg/ddt315
Appears in Collections:Paediatrics publications

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