Evidence of disrupted rhombic lip development in the pathogenesis of Dandy–Walker malformation
| العنوان: | Evidence of disrupted rhombic lip development in the pathogenesis of Dandy–Walker malformation |
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| المؤلفون: | Andrew E. Timms, Danilo Dubocanin, Cira Di Gioia, Rosa Russo, Derek Dang, Kathleen J. Millen, Ozgur Oztekin, Lucia Manganaro, Alexandria H Sjoboen, Brian D Davis, Kimberly A. Aldinger, Fabien Guimiot, Ian A. Glass, Jake Millman, Evelina Silvestri, Homa Adle-Biassette, Mei Deng, Tarika Sivakumar, Parthiv Haldipur, Ferechté Razavi, Kshitij Mankad, Nathalie Roux, Joseph R. Siebert, Silvia Bernardo, Giulia Petrilli, Debora Kidron, Jasmine T. Plummer |
| المصدر: | Acta Neuropathol |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cerebellum, cerebellum, Developmental Disabilities, Biology, Nervous System Malformations, Article, cerebellar vermis hypoplasia, Dandy–Walker malformation, development, rhombic lip, Pathology and Forensic Medicine, Fetal Development, Pathogenesis, Cellular and Molecular Neuroscience, Fetus, medicine, Humans, Rhombic lip, Laser capture microdissection, Progenitor, Infant, Newborn, Anatomy, medicine.disease, Hypoplasia, medicine.anatomical_structure, Dysplasia, Case-Control Studies, Immunohistochemistry, Neurology (clinical), Dandy-Walker Syndrome |
| الوصف: | Dandy-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. |
| تدمد: | 1432-0533 0001-6322 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9e193f803997c3ba3aa6cd76ca148ff1Test https://doi.org/10.1007/s00401-021-02355-7Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9e193f803997c3ba3aa6cd76ca148ff1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14320533 00016322 |
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