Rgs16 and Rgs8 in embryonic endocrine pancreas and mouse models of diabetes

Abstract

SUMMARYDiabetes is characterized by the loss, or gradual dysfunction, of insulin-producing pancreatic -cells. Although -cells can replicate in younger adults, the available diabetes therapies do not specifically target -cell regeneration. Novel approaches are needed to discover new therapeutics and to understand the contributions of endocrine progenitors and -cell regeneration during islet expansion. Here, we show that the regulators of G protein signaling Rgs16 and Rgs8 are expressed in pancreatic progenitor and endocrine cells during development, then extinguished in adults, but reactivated in models of both type 1 and type 2 diabetes. Exendin-4, a glucagon-like peptide 1 (Glp-1)/incretin mimetic that stimulates -cell expansion, insulin secretion and normalization of blood glucose levels in diabetics, also promoted re-expression of Rgs16::GFP within a few days in pancreatic ductalassociated cells and islet -cells. These findings show that Rgs16::GFP and Rgs8::GFP are novel and early reporters of G protein-coupled receptor (GPCR)-stimulated -cell expansion after therapeutic treatment and in diabetes models. Rgs16 and Rgs8 are likely to control aspects of islet progenitor cell activation, differentiation and -cell expansion in embryos and metabolically stressed adults.

Regulator of G Protein Signaling (RGS16) Inhibits Hepatic Fatty Acid Oxidation in a Carbohydrate Response Element-binding Protein (ChREBP)-dependent Manner

“…Rgs16 and its tandemly duplicated paralog, Rgs8 (40), may be general regulators of glucose homeostasis because these genes are expressed not only in liver during fasting but also in islet beta cells during postnatal and embryonic development and even in pancreatic progenitor cells at the initiation of pancreas development (41). Importantly, expression in adult pancreas is suppressed until periods of high insulin demand, as in mouse models of type 1 and type 2 diabetes, and during midgestation in pregnant females.…”

Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome

“…This approach successfully filters out highly expressed genes in contaminating cell types (e.g., SST, GCG from somatostatin, and glucagon cells contaminating the beta cell population), otherwise mistaken as key players in the expression signature of beta cells. In addition to known beta-cell-specific transcripts (INS, IGF2, PDX1) we highlight further targets, some featured already in a microarray analysis of sorted islet cells (Dorrell et al 2011b), e.g., RGS16, negative regulator of G-protein signaling, involved in endocrine pancreas development and re-expressed in adult cells in response to GLP-1 (Villasenor et al 2010); ADCYAP1, pituitary adenylate cyclase activating polypeptide 1, involved in insulin secretion and beta cell regeneration/proliferation (Sakurai et al 2011); HADH, hydroxyacyl-CoA dehydrogenase, negative regulator of insulin secretion (Hardy et al 2007) associated with Alzheimer's (Nicolls et al 2003), which is in turn associated with diabetes. Many other genes however have not been described before in the context of beta cells, including: NPTX2, neuronal pentraxin 2, found in neuronal cells and gliomas but also shown to be frequently downregulated in pancreatic cancers (Zhang et al 2012); TSPAN1, tetraspanin 1, which can associate with alpha6.beta1 integrin and promote FAK phosphorylation (Huang et al 2008) shown by us to be involved in insulin secretion (Rondas et al 2011); GPM6A, neuronal membrane glycoprotein of unknown function but identified as a beta cell marker in sorted mouse islet cells (Dorrell et al 2011a); BMP5, bone morphogenic protein 5, implicated in pancreas and fetal beta cell development ( Jiang et al 2002); and P2RY1, purinergic receptor through which ADP and ATP modulate insulin secretion (Fernandez-Alvarez et al 2001).…”

Cell dynamics in fetal intestinal epithelium: implications for intestinal growth and morphogenesis

“…Intestinal epithelial dynamics polarity (Mailleux et al, 2008;Sternlicht, 2006;Tucker, 2007;Villasenor et al, 2010;Walker et al, 2008). To further investigate this, we examined the Golgi marker Gm130 (Golga2 -Mouse Genome Informatics).…”

“…These models are supported by ultrastructural studies that link the initiation of epithelial remodeling to the de novo formation of apical surfaces at so-called secondary lumina located deep within stratified epithelial layers (Madara et al, 1981;Mathan et al, 1976;Toyota et al, 1989) and by recent studies in the zebrafish (Bagnat et al, 2007) and mouse (Saotome et al, 2004) intestine that have pinpointed some of the genes required for this process. Dynamic changes in cell polarity and the fusion of a network of secondary lumina in the context of a transient stratified epithelium were recently shown to drive the formation of murine pancreatic acini (Villasenor et al, 2010). However, in a pseudostratified epithelium, in which all cells already have an apical surface facing the lumen, a more likely mechanism driving remodeling would be cell shape change, coupled with expansion of the existing luminal surface.…”