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Puri, S.* ; Maachi, H. ; Nair, G.* ; Russ, H.A.* ; Chen, R.* ; Pulimeno, P.* ; Cutts, Z.* ; Ntranos, V.* ; Hebrok, M.

Sox9 regulates alternative splicing and pancreatic beta cell function.

Nat. Commun. 15:588 (2024)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Despite significant research, mechanisms underlying the failure of islet beta cells that result in type 2 diabetes (T2D) are still under investigation. Here, we report that Sox9, a transcriptional regulator of pancreas development, also functions in mature beta cells. Our results show that Sox9-depleted rodent beta cells have defective insulin secretion, and aging animals develop glucose intolerance, mimicking the progressive degeneration observed in T2D. Using genome editing in human stem cells, we show that beta cells lacking SOX9 have stunted first-phase insulin secretion. In human and rodent cells, loss of Sox9 disrupts alternative splicing and triggers accumulation of non-functional isoforms of genes with key roles in beta cell function. Sox9 depletion reduces expression of protein-coding splice variants of the serine-rich splicing factor arginine SRSF5, a major splicing enhancer that regulates alternative splicing. Our data highlight the role of SOX9 as a regulator of alternative splicing in mature beta cell function.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Transcriptional Network; Progenitor Cells; Stem-cells; Endocrine; Expression; Insulin; Dedifferentiation; Inactivation; Pdx1; Differentiation
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 15, Issue: 1, Pages: , Article Number: 588 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute for Diabetes und Organoid Technology (IDOT)
Grants JDRF postdoctoral fellowship
Kraft Family Fellowship
UCSF Flow Cytometry Core
JDRF