Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis.

Autor:	Mastropasqua F; Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institute, Region Stockholm, 17164 Stockholm, Sweden.; Astrid Lindgren Children's Hospital , Karolinska University Hospital, Region Stockholm, 17164 Stockholm, Sweden., Oksanen M; Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institute, Region Stockholm, 17164 Stockholm, Sweden.; Astrid Lindgren Children's Hospital , Karolinska University Hospital, Region Stockholm, 17164 Stockholm, Sweden., Soldini C; Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institute, Region Stockholm, 17164 Stockholm, Sweden.; Astrid Lindgren Children's Hospital , Karolinska University Hospital, Region Stockholm, 17164 Stockholm, Sweden., Alatar S; Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institute, Region Stockholm, 17164 Stockholm, Sweden.; Astrid Lindgren Children's Hospital , Karolinska University Hospital, Region Stockholm, 17164 Stockholm, Sweden., Arora A; Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institute, Region Stockholm, 17164 Stockholm, Sweden.; Astrid Lindgren Children's Hospital , Karolinska University Hospital, Region Stockholm, 17164 Stockholm, Sweden., Ballarino R; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17164 Stockholm, Sweden.; Science for Life Laboratory, Tomtebodavägen 23A, 17165 Solna, Sweden.; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17165 Stockholm, Sweden., Molinari M; Department of Neuroscience, Karolinska Institutet, 17176 Solna, Sweden., Agostini F; Science for Life Laboratory, Tomtebodavägen 23A, 17165 Solna, Sweden.; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17165 Stockholm, Sweden., Poulet A; Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA., Watts M; Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institute, Region Stockholm, 17164 Stockholm, Sweden.; Astrid Lindgren Children's Hospital , Karolinska University Hospital, Region Stockholm, 17164 Stockholm, Sweden., Rabkina I; Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institute, Region Stockholm, 17164 Stockholm, Sweden.; Astrid Lindgren Children's Hospital , Karolinska University Hospital, Region Stockholm, 17164 Stockholm, Sweden., Becker M; Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institute, Region Stockholm, 17164 Stockholm, Sweden.; Astrid Lindgren Children's Hospital , Karolinska University Hospital, Region Stockholm, 17164 Stockholm, Sweden., Li D; Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institute, Region Stockholm, 17164 Stockholm, Sweden.; Astrid Lindgren Children's Hospital , Karolinska University Hospital, Region Stockholm, 17164 Stockholm, Sweden., Anderlid BM; Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden.; Department of Clinical Genetics, Karolinska University Hospital, 17164 Stockholm, Sweden., Isaksson J; Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institute, Region Stockholm, 17164 Stockholm, Sweden.; Department of Medical Sciences, Child and Adolescent Psychiatry Unit, Uppsala University, 75309 Uppsala, Sweden., Lundin Remnelius K; Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institute, Region Stockholm, 17164 Stockholm, Sweden., Moslem M; Department of Neuroscience, Karolinska Institutet, 17176 Solna, Sweden., Jacob Y; Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA., Falk A; Department of Neuroscience, Karolinska Institutet, 17176 Solna, Sweden.; Lund Stem Cell Center, Lund University, 22100 Lund, Sweden., Crosetto N; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17164 Stockholm, Sweden.; Science for Life Laboratory, Tomtebodavägen 23A, 17165 Solna, Sweden.; Human Technopole, Viale Rita Levi-Montalcini 1, 20157 Milan, Italy., Bienko M; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17164 Stockholm, Sweden.; Science for Life Laboratory, Tomtebodavägen 23A, 17165 Solna, Sweden.; Human Technopole, Viale Rita Levi-Montalcini 1, 20157 Milan, Italy., Santini E; Department of Neuroscience, Karolinska Institutet, 17176 Solna, Sweden., Borgkvist A; Department of Neuroscience, Karolinska Institutet, 17176 Solna, Sweden., Bölte S; Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institute, Region Stockholm, 17164 Stockholm, Sweden.; Astrid Lindgren Children's Hospital , Karolinska University Hospital, Region Stockholm, 17164 Stockholm, Sweden.; Curtin Autism Research Group , Curtin School of Allied Health, Curtin University, 6845 Perth, Western Australia.; Child and Adolescent Psychiatry , Stockholm Health Care Services, Region Stockholm, 10431 Stockholm, Sweden., Tammimies K; Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institute, Region Stockholm, 17164 Stockholm, Sweden.; Astrid Lindgren Children's Hospital , Karolinska University Hospital, Region Stockholm, 17164 Stockholm, Sweden.
Jazyk:	angličtina
Zdroj:	Biology open [Biol Open] 2023 Oct 15; Vol. 12 (10). Date of Electronic Publication: 2023 Oct 10.
DOI:	10.1242/bio.060113
Abstrakt:	Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs). HNRNPU is widely expressed in the human brain and shows the highest postnatal expression in the cerebellum. Recent studies have investigated the role of HNRNPU in cerebral cortical development, but the effects of HNRNPU deficiency on cerebellar development remain unknown. Here, we describe the molecular and cellular outcomes of HNRNPU locus deficiency during in vitro neural differentiation of patient-derived and isogenic neuroepithelial stem cells with a hindbrain profile. We demonstrate that HNRNPU deficiency leads to chromatin remodeling of A/B compartments, and transcriptional rewiring, partly by impacting exon inclusion during mRNA processing. Genomic regions affected by the chromatin restructuring and host genes of exon usage differences show a strong enrichment for genes implicated in epilepsies, intellectual disability, and autism. Lastly, we show that at the cellular level HNRNPU downregulation leads to an increased fraction of neural progenitors in the maturing neuronal population. We conclude that the HNRNPU locus is involved in delayed commitment of neural progenitors to differentiate in cell types with hindbrain profile. Competing Interests: Competing interests M.B. is a full-time employee of Bayer AG, Germany. S.B. declares no direct conflict of interest related to this article. He discloses that he has, in the last 3 years, acted as an author, consultant, or lecturer for Medice and Roche. He receives royalties for textbooks and diagnostic tools from Hogrefe, and Liber. S.B. is shareholder in SB Education/Psychological Consulting AB and NeuroSupportSolutions International AB. The other authors have no conflicts to declare. (© 2023. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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