title: Regulation of SPRY3 by X chromosome and PAR2-linked promoters in an autism susceptibility region.
abstract: Sprouty proteins are regulators of cell growth and branching morphogenesis. Unlike mouse Spry3, which is X-linked, human SPRY3 maps to the pseudoautosomal region 2; however, the human Y-linked allele is not expressed due to epigenetic silencing by an unknown mechanism. SPRY3 maps adjacent to X-linked Trimethyllysine hydroxylase epsilon (TMLHE), recently identified as an autism susceptibility gene. We report that Spry3 is highly expressed in central and peripheral nervous system ganglion cells in mouse and human, including cerebellar Purkinje cells and retinal ganglion cells. Transient over-expression or knockdown of Spry3 in cultured mouse superior cervical ganglion cells inhibits and promotes, respectively, neurite growth and branching. A 0.7 kb gene fragment spanning the human SPRY3 transcriptional start site recapitulates the endogenous Spry3-expression pattern in LacZ reporter mice. In the human and mouse the SPRY3 promoter contains an AG-rich repeat and we found co-expression, and promoter binding and/or regulation of SPRY3 expression by transcription factors MAZ, EGR1, ZNF263 and PAX6. We identified eight alleles of the human SPRY3 promoter repeat in Caucasians, and similar allele frequencies in autism families. We characterized multiple SPRY3 transcripts originating at two CpG islands in the X-linked F8A3-TMLHE region, suggesting X chromosome regulation of SPRY3. These findings provide an explanation for differential regulation of X and Y-linked SPRY3 alleles. In addition, the presence of a SPRY3 transcript exon in a previously described X chromosome deletion associated with autism, and the cerebellar interlobular variation in Spry3 expression coincident with the reported pattern of Purkinje cell loss in autism, suggest SPRY3 as a candidate susceptibility locus for autism.
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Western Gateway Building, Western Road, Cork, Ireland.
authors.forename: Zhenfei
authors.initials: Z
authors.lastname: Ning
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Western Gateway Building, Western Road, Cork, Ireland.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McLellan
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Western Gateway Building, Western Road, Cork, Ireland.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ball
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Western Gateway Building, Western Road, Cork, Ireland.
authors.forename: Freda
authors.initials: F
authors.lastname: Wynne
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Western Gateway Building, Western Road, Cork, Ireland.
authors.forename: Cora
authors.initials: C
authors.lastname: O'Neill
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Western Gateway Building, Western Road, Cork, Ireland.
authors.forename: Walter
authors.initials: W
authors.lastname: Mills
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Quinn
authors.affiliation: MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Kleinjan
authors.affiliation: Department of Psychiatry, Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Anney
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Sir Graeme Davies Building, Glasgow G12 8TA, UK and.
authors.forename: Ruaidhre J
authors.initials: RJ
authors.lastname: Carmody
authors.affiliation: Department of Anatomy and Neuroscience, Biosciences Institute, University College Cork, College Road, Cork, Ireland.
authors.forename: Gerard
authors.initials: G
authors.lastname: O'Keeffe
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Western Gateway Building, Western Road, Cork, Ireland, t.moore@ucc.ie.
authors.forename: Tom
authors.initials: T
authors.lastname: Moore
mesh_terms: D000483:Alleles; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D001482:Base Composition; D001483:Base Sequence; D002460:Cell Line; D002531:Cerebellum / Q000378:metabolism; D041321:Chromosomes, Human, X; D018899:CpG Islands; D019175:DNA Methylation; D004195:Disease Models, Animal; D005091:Exons; D005724:Ganglia / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D050172:Genes, X-Linked; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016501:Neurites / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D044464:Receptor, PAR-2 / Q000235:genetics*; D016415:Sequence Alignment; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D044464:Receptor, PAR-2; C407225:SPRY3 protein, human; D014157:Transcription Factors