Opposite expression patterns of Spry3 and p75NTR in cerebellar vermis suggest a male-specific mechanism of autism pathogenesis

dc.contributor.authorNing, Zhenfei
dc.contributor.authorWilliams, John M.
dc.contributor.authorKumari, Romika
dc.contributor.authorBaranov, Pavel V.
dc.contributor.authorMoore, Tom
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2019-11-20T05:47:22Z
dc.date.available2019-11-20T05:47:22Z
dc.date.issued2019-06-18
dc.description.abstractAutism is a genetically complex neurobehavioral disorder with a population prevalence of more than 1%. Cerebellar abnormalities, including Purkinje cell deficits in the vermis, are consistently reported and rodent models of cerebellar dysfunction exhibit features analogous to human autism. We previously analysed the regulation and expression of the pseudoautosomal region 2 gene SPRY3, which is adjacent to X chromosome-linked TMLHE, a known autism susceptibility gene. SPRY3 is a regulator of branching morphogenesis and is strongly expressed in Purkinje cells. We previously showed that mouse Spry3 is not expressed in cerebellar vermis lobules VI-VII and X, regions which exhibit significant Purkinje cell loss or abnormalities in autism. However, these lobules have relatively high expression of p75NTR, which encodes a neurotrophin receptor implicated in autism. We propose a mechanism whereby inappropriate SPRY3 expression in these lobules could interact with TrkB and p75NTR signalling pathways resulting in Purkinje cell pathology. We report preliminary characterisation of X and Y chromosome-linked regulatory sequences upstream of SPRY3, which are polymorphic in the general population. We suggest that an OREG-annotated region on chromosome Yq12 ~60 kb from SPRY3 acts as a silencer of Y-linked SPRY3 expression. Deletion of a β-satellite repeat, or alterations in chromatin structure in this region due to trans-acting factors, could affect the proposed silencing function, leading to reactivation and inappropriate expression of Y-linked SPRY3. This proposed male-specific mechanism could contribute to the male bias in autism prevalence.en
dc.description.sponsorshipIrish Transgenic Network Awarden
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid416en
dc.identifier.citationNing, Z., Williams, J.M., Kumari, R., Baranov, P.V. and Moore, T., 2019. Opposite expression patterns of Spry3 and p75NTR in cerebellar vermis suggest a male-specific mechanism of autism pathogenesis. Frontiers in Psychiatry, 10, (416). DOI:10.3389/fpsyt.2019.00416en
dc.identifier.doi10.3389/fpsyt.2019.00416en
dc.identifier.eissn1664-0640
dc.identifier.endpage16en
dc.identifier.journaltitleFrontiers in Psychiatryen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/9135
dc.identifier.volume10en
dc.language.isoenen
dc.publisherFrontiers Mediaen
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Technology and Innovation Development Award (TIDA)/13/TIDA/B2659/IE/Use of PSG1 protein as a therapeutic agent in wound healing/en
dc.relation.urihttps://www.frontiersin.org/articles/10.3389/fpsyt.2019.00416
dc.rights© 2019 Ning, Williams, Kumari, Baranov and Mooreen
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectAutismen
dc.subjectCerebellumen
dc.subjectSPRY3en
dc.subjectp75NTRen
dc.subjectPseudoautosomal regionen
dc.subjectTMLHEen
dc.subjectCarnitineen
dc.titleOpposite expression patterns of Spry3 and p75NTR in cerebellar vermis suggest a male-specific mechanism of autism pathogenesisen
dc.title.alternativeSpry3 and p75NTR in autismen
dc.typeArticle (peer-reviewed)en
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