The Role of SOX9 Transcription Factor in Pancreatic and Duodenal Development

Abstract

Progenitor expansion during development is a highly regulated process dictating the final organ size, while expansion of specific progenitor populators can adjust the final cellular composition of the organ. Understanding factors involved in these pathways is required to develop cell-based therapies such as β-cell transplantation for conditions such as diabetes mellitus. One versatile factor controlling both processes as well as a network of other proteins involved in pancreatic and duodenal development is the transcription factor SOX9. This review will focus on a comparison of SOX9 function during progenitor expansion and differentiation in the developing pancreas and duodenum with specific focus on endocrine development. During human pancreatic development, SOX9 functions in a dose-dependent manner to regulate epithelial progenitor expansion and endocrine differentiation. SOX9 expression is eventually limited to a subset of ductal and centroacinar cells, hypothesized to be the pancreatic stem cell compartment. Similarly, during duodenal development, SOX9 is expressed in most early epithelial progenitors and becomes gradually restricted to proliferative progenitors in the lower crypts, as well as mature Paneth and enteroendocrine cells indicating some differences in functional roles. However, in both developmental contexts, SOX9 is involved in pathways responsible for cellular proliferation and differentiation, such as Notch and Wnt. With its adaptable and central function in progenitor control, SOX9 represents an attractive target for manipulation for in vitro progenitor expansion and differentiation meriting further investigation.

Sox9b is a mediator of retinoic acid signaling restricting endocrine progenitor differentiation

“…Furthermore we diminished Sox9b activity in adult zebrafish leads to accelerated recovery of blood-glucose levels following β-cell ablation concomitant with enhanced progenitor differentiation. Discovering that diminished Sox9b activity leads to expedited differentiation is consistent with the findings of others that established Sox9 homologs as being essential for maintenance of progenitor populations (Belo et al, 2013; Seymour et al, 2007). We are now exploring a model where Sox9b, via its downstream targets, maintains CACs by promoting self-renewal and restricting differentiation.…”

Centroacinar cells: At the center of pancreas regeneration

“…The signaling molecules regulating the CAC response to injury are unknown, and analysis of CACs during both regeneration and homeostasis can begin to address this issue. Furthermore, several groups have hypothesized the existence of a pancreas stem cell population (Belo et al, 2013; Furuyama et al, 2011; Parsons et al, 2009; Stanger et al, 2005; Wang et al, 2011). CACs do express Sox9, a known regulator of hair follicle and intestinal stem cells (Bastide et al, 2007; Blache et al, 2004; Kadaja et al, 2014; Nowak et al, 2008).…”

The Sox transcriptional factors: Functions during intestinal development in vertebrates

“…Increasing evidence points to the involvement of Sox genes in mammalian intestinal development and a few excellent reviews have been published on this subject [106–108]. One of the most studied in the gastrointestinal tract is Sox9, a member of the SoxE subfamily.…”

“…One of the most studied in the gastrointestinal tract is Sox9, a member of the SoxE subfamily. Sox9 was first described as the gene whose haploinsufficiency leads to Campomelic Dysplasia with symptoms including XY sex reversal, skeletal defects and pancreatic endocrine defects [108–113]. It has subsequently been shown to be important for the development of many organs and tissues, including the intestine [108].…”

“…Sox9 was first described as the gene whose haploinsufficiency leads to Campomelic Dysplasia with symptoms including XY sex reversal, skeletal defects and pancreatic endocrine defects [108–113]. It has subsequently been shown to be important for the development of many organs and tissues, including the intestine [108]. During mouse development, Sox9 is expressed throughout duodenal epithelium as early as embryonic day 13.5 (E13.5) and subsequently restricted to the proliferating epithelial cells, the Paneth and enteroendocrine cells around E18.5, and finally only in the crypt of the adult intestine [114].…”