title: Sox9b is a mediator of retinoic acid signaling restricting endocrine progenitor differentiation.
abstract: Centroacinar cells (CACs) are ductal Notch-responsive progenitors that in the larval zebrafish pancreas differentiate to form new islets and ultimately contribute to the majority of the adult endocrine mass. Uncovering the mechanisms regulating CAC differentiation will facilitate understanding how insulin-producing β cells are formed. Previously we reported retinoic acid (RA) signaling and Notch signaling both regulate larval CAC differentiation, suggesting a shared downstream intermediate. Sox9b is a transcription factor important for islet formation whose expression is upregulated by Notch signaling in larval CACs. Here we report that sox9b expression in larval CACs is also regulated by RA signaling. Therefore, we hypothesized that Sox9b is an intermediate between both RA- and Notch-signaling pathways. In order to study the role of Sox9b in larval CACs, we generated two cre/lox based transgenic tools, which allowed us to express full-length or truncated Sox9b in larval CACs. In this way we were able to perform spatiotemporal-controlled Sox9b gain- and loss-of-function studies and observe the subsequent effect on progenitor differentiation. Our results are consistent with Sox9b regulating CAC differentiation by being a downstream intermediate of both RA- and Notch-signaling pathways. We also demonstrate that adult zebrafish with only one functional allele of sox9b undergo accelerated β-cell regeneration, an observation consistent with sox9b regulating CAC differentiation in adults.
authors: McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA.
authors: Wei
authors: W
authors: Huang
authors: McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA.
authors: Rebecca L
authors: RL
authors: Beer
authors: McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA.
authors: Fabien
authors: F
authors: Delaspre
authors: McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA.
authors: Guangliang
authors: G
authors: Wang
authors: McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA.
authors: Hannah E
authors: HE
authors: Edelman
authors: Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA.
authors: Hyewon
authors: H
authors: Park
authors: Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA.
authors: Mizuki
authors: M
authors: Azuma
authors: McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA; Department of Surgery, Johns Hopkins University School of Medicine, 733 N. Broadway, 470 Miller Research Building, Baltimore, MD 21205, USA.
authors: Michael J
authors: MJ
authors: Parsons
mesh_terms: D000483:Alleles; D000818:Animals; D001786:Blood Glucose / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics* / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007814:Larva / Q000254:growth & development; D010179:Pancreas / Q000196:embryology*; D051880:Receptors, Notch / Q000378:metabolism; D012038:Regeneration / Q000235:genetics; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D051880:Receptors, Notch; D055758:SOX9 Transcription Factor; C504919:Sox9b protein, zebrafish; D029961:Zebrafish Proteins; D014212:Tretinoin
keywords: Differentiation; Endocrine; Pancreas; Progenitors; Sox9