Abstract
The HMG box transcription factor Sox9 plays a critical role in progenitor cell expansion during pancreas organogenesis and is required for proper endocrine cell development in the embryo. Based on in vitro studies it has been suggested that Sox9 controls expression of a network of important developmental regulators, including Tcf2/MODY5, Hnf6, and Foxa2, in pancreatic progenitor cells. Here, we sought to: 1) determine whether Sox9 regulates this transcriptional network in vivo and 2) investigate whether reduced Sox9 gene dosage leads to impaired glucose homeostasis in adult mice. Employing two genetic models of temporally-controlled Sox9 inactivation in pancreatic progenitor cells, we demonstrate that contrary to in vitro findings, Sox9 is not required for Tcf2, Hnf6, or Foxa2 expression in vivo. Moreover, our analysis revealed a novel role for Sox9 in maintaining the expression of Pdx1/MODY4, which is an important transcriptional regulator of beta-cell development. We further show that reduced beta-cell mass in Sox9-haploinsufficient mice leads to glucose intolerance during adulthood. Sox9-haploinsufficient mice displayed 50% reduced beta-cell mass at birth, which recovered partially via a compensatory increase in beta-cell proliferation early postnatally. Endocrine islets from mice with reduced Sox9 gene dosage exhibited normal glucose stimulated insulin secretion. Our findings show Sox9 plays an important role in endocrine development by maintaining Ngn3 and Pdx1 expression. Glucose intolerance in Sox9-haploinsufficient mice suggests that mutations in Sox9 could play a role in diabetes in humans.
Highlights
Both proper neogenesis of mature endocrine cells during embryonic pancreas development and the maintenance of an adequate number of functional islets during adulthood are necessary for normal glucose homeostasis
Sox9 expression parallels that of a network of factors upstream of Neurogenin 3 (Ngn3) Previously, we showed that Sox9+/Dpan embryos exhibit a 50%
To test whether this regulation occurs in vivo, we first examined whether the expression domain of Sox9 coincides with those of these transcription factors in multipotent progenitor cells (MPCs)
Summary
Both proper neogenesis of mature endocrine cells during embryonic pancreas development and the maintenance of an adequate number of functional islets during adulthood are necessary for normal glucose homeostasis. Endocrine and exocrine (ductal and acinar) cells of the pancreas derive from multipotent progenitor cells (MPCs) expressing the transcription factors Pdx1 [1], Ptf1a [2], Sox9 [3] and Tcf (Hnf1b) [4]. Pancreas-specific Sox9haploinsufficiency in Pdx1-Cre; Sox9+/flox (Sox9+/Dpan) mice results in a 50% decrease in both Ngn3+ endocrine progenitors and endocrine cells at birth [14]. Though Sox has been shown to bind the Ngn promoter in embryonic pancreas in vivo [14], in vitro studies have implied that it regulates Hnf, Tcf, and Foxa and is critical for activating and/or maintaining an entire network of endocrine differentiation genes [15]. By employing temporally controlled Sox inactivation strategies in mice, we sought to determine which components of the pancreatic transcriptional network are regulated by Sox in vivo
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