title: A Sox9/Fgf feed-forward loop maintains pancreatic organ identity.
abstract: All mature pancreatic cell types arise from organ-specific multipotent progenitor cells. Although previous studies have identified cell-intrinsic and -extrinsic cues for progenitor cell expansion, it is unclear how these cues are integrated within the niche of the developing organ. Here, we present genetic evidence in mice that the transcription factor Sox9 forms the centerpiece of a gene regulatory network that is crucial for proper organ growth and maintenance of organ identity. We show that pancreatic progenitor-specific ablation of Sox9 during early pancreas development causes pancreas-to-liver cell fate conversion. Sox9 deficiency results in cell-autonomous loss of the fibroblast growth factor receptor (Fgfr) 2b, which is required for transducing mesenchymal Fgf10 signals. Likewise, Fgf10 is required to maintain expression of Sox9 and Fgfr2 in epithelial progenitors, showing that Sox9, Fgfr2 and Fgf10 form a feed-forward expression loop in the early pancreatic organ niche. Mirroring Sox9 deficiency, perturbation of Fgfr signaling in pancreatic explants or genetic inactivation of Fgf10 also result in hepatic cell fate conversion. Combined with previous findings that Fgfr2b or Fgf10 are necessary for pancreatic progenitor cell proliferation, our results demonstrate that organ fate commitment and progenitor cell expansion are coordinately controlled by the activity of a Sox9/Fgf10/Fgfr2b feed-forward loop in the pancreatic niche. This self-promoting Sox9/Fgf10/Fgfr2b loop may regulate cell identity and organ size in a broad spectrum of developmental and regenerative contexts.
authors.affiliation: Departments of Pediatrics and Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093-0695, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Seymour
authors.forename: Hung Ping
authors.initials: HP
authors.lastname: Shih
authors.forename: Nisha A
authors.initials: NA
authors.lastname: Patel
authors.forename: Kristine K
authors.initials: KK
authors.lastname: Freude
authors.forename: Ruiyu
authors.initials: R
authors.lastname: Xie
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lim
authors.forename: Maike
authors.initials: M
authors.lastname: Sander
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D010179:Pancreas / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2