Evidence of disrupted rhombic lip development in the pathogenesis of Dandy-Walker malformation

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dc.authoridAldinger, Kimberly / 0000-0002-5406-8911
dc.authoridOztekin, Ozgur / 0000-0002-0092-5260
dc.authoridHALDIPUR, PARTHIV / 0000-0003-2865-8683
dc.authorscopusid50262012900
dc.authorscopusid26633467400
dc.authorscopusid8263053700
dc.authorscopusid57226489437
dc.authorscopusid57226491676
dc.authorscopusid57226496450
dc.authorscopusid57193136498
dc.authorwosidAldinger, Kimberly/ABB-1561-2020
dc.authorwosidOztekin, Ozgur/AAC-4801-2021
dc.contributor.authorHaldipur, Parthiv
dc.contributor.authorBernardo, Silvia
dc.contributor.authorAldinger, Kimberly A.
dc.contributor.authorSivakumar, Tarika
dc.contributor.authorMillman, Jake
dc.contributor.authorSjoboen, Alexandria H.
dc.contributor.authorMillen, Kathleen J.
dc.contributor.authorÖztekin, Özgür
dc.date.accessioned2022-02-15T16:57:50Z
dc.date.available2022-02-15T16:57:50Z
dc.date.issued2021
dc.departmentBakırçay Üniversitesien_US
dc.description.abstractDandy-Walker malformation (DWM) and Cerebellar vermis hypoplasia (CVH) are commonly recognized human cerebellar malformations diagnosed following ultrasound and antenatal or postnatal MRI. Specific radiological criteria are used to distinguish them, yet little is known about their differential developmental disease mechanisms. We acquired prenatal cases diagnosed as DWM and CVH and studied cerebellar morphobiometry followed by histological and immunohistochemical analyses. This was supplemented by laser capture microdissection and RNA-sequencing of the cerebellar rhombic lip, a transient progenitor zone, to assess the altered transcriptome of DWM vs control samples. Our radiological findings confirm that the cases studied fall within the accepted biometric range of DWM. Our histopathological analysis points to reduced foliation and inferior vermian hypoplasia as common features in all examined DWM cases. We also find that the rhombic lip, a dorsal stem cell zone that drives the growth and maintenance of the posterior vermis is specifically disrupted in DWM, with reduced proliferation and self-renewal of the progenitor pool, and altered vasculature, all confirmed by transcriptomics analysis. We propose a unified model for the developmental pathogenesis of DWM. We hypothesize that rhombic lip development is disrupted through either aberrant vascularization and/or direct insult which causes reduced proliferation and failed expansion of the rhombic lip progenitor pool leading to disproportionate hypoplasia and dysplasia of the inferior vermis. Timing of insult to the developing rhombic lip (before or after 14 PCW) dictates the extent of hypoplasia and distinguishes DWM from CVH.en_US
dc.description.sponsorshipNational Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 NS080390, R01 NS095733]; National Ataxia Foundation Young Investigator Research Grant; Brain and Behavior Research Foundation Young Investigator Award [28956]; Franklin Research Award by the American Philosophical Societyen_US
dc.description.sponsorshipNational Institutes of Health R01 NS080390 and R01 NS095733 (KJM). National Ataxia Foundation Young Investigator Research Grant, Brain and Behavior Research Foundation Young Investigator Award #28956, and Franklin Research Award by the American Philosophical Society (PH).en_US
dc.identifier.doi10.1007/s00401-021-02355-7
dc.identifier.endpage776en_US
dc.identifier.issn0001-6322
dc.identifier.issn1432-0533
dc.identifier.issue4en_US
dc.identifier.pmid34347142en_US
dc.identifier.scopus2-s2.0-85111710391en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage761en_US
dc.identifier.urihttps://doi.org/10.1007/s00401-021-02355-7
dc.identifier.urihttps://hdl.handle.net/20.500.14034/285
dc.identifier.volume142en_US
dc.identifier.wosWOS:000681169200001en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherSpringeren_US
dc.relation.journalActa Neuropathologicaen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectDandy-Walker malformationen_US
dc.subjectCerebellumen_US
dc.subjectCerebellar vermis hypoplasiaen_US
dc.subjectRhombic lipen_US
dc.subjectDevelopmenten_US
dc.subjectCerebellar Vermisen_US
dc.subjectClassificationen_US
dc.subjectFoxc1en_US
dc.titleEvidence of disrupted rhombic lip development in the pathogenesis of Dandy-Walker malformationen_US
dc.typeArticleen_US

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