Groucho co-repressor proteins regulate β cell development and proliferation by repressing Foxa1 in the developing mouse pancreas

Abstract

Groucho-related genes (GRGs) are transcriptional co-repressors that are crucial for many developmental processes. Several essential pancreatic transcription factors are capable of interacting with GRGs; however, the in vivo role of GRG-mediated transcriptional repression in pancreas development is still not well understood. In this study, we used complex mouse genetics and transcriptomic analyses to determine that GRG3 is essential for β cell development, and in the absence of Grg3 there is compensatory upregulation of Grg4. Grg3/4 double mutant mice have severe dysregulation of the pancreas gene program with ectopic expression of canonical liver genes and Foxa1, a master regulator of the liver program. Neurod1, an essential β cell transcription factor and predicted target of Foxa1, becomes downregulated in Grg3/4 mutants, resulting in reduced β cell proliferation, hyperglycemia, and early lethality. These findings uncover novel functions of GRG-mediated repression during pancreas development.

The role of FOXA family transcription factors in glucolipid metabolism and NAFLD

“…Neurod1, leading to loss of Β cell proliferation, early lethality, and hyperglycemia (38). Consistent with genetic screening results in patients with congenital hyperinsulinemia (39), FOXA2 inactivation in mature Β cells induced hyperinsulinemia and hypoglycemia.…”

“…The intrinsic reason for this phenomenon is that deficiency of FOXA1 causes increased expression of the uncoupling protein 2 (UCP2), which results in mitochondrial oxidative phosphorylation being partly uncoupled, the change in glucose concentrations is no longer efficiently converted to increased ATP levels, further affecting the subsequent closure of ATP-dependent potassium channels and the inward flow of calcium ions, ultimately inhibiting insulin release. In conclusion, although FOXA1 is not required for the initial specification of pancreatic Β cell, the terminal differentiation to fully mature Β cell is dependent on FOXA1 expression ( 37 ).In addition, lack of Groucho-related gene3/4-mediated repression leads to ectopic expression of FOXA1, which represses the expression of the Β cell transcription factor gene Neurod1, leading to loss of Β cell proliferation, early lethality, and hyperglycemia ( 38 ).…”

Roles of transducin-like enhancer of split (TLE) family proteins in tumorigenesis and immune regulation

“…Frontiers in Cell and Developmental Biology frontiersin.org cells, whereas in cervical squamous metaplasia and carcinomas, the expression levels of these TLE members are elevated (Liu et al, 1996). In addition, TLE members were found to be expressed in a complementary pattern in developing mouse neurons and the pancreas (Yao et al, 1998;Theis et al, 2021). These results suggest that TLE expression is spatiotemporally regulated and that different TLEs may exhibit specific activity in different cell contexts.…”

“…As mentioned earlier, TLEs play vital roles in the development of the lung and pancreas (Metzger et al, 2012;Ramasamy et al, 2016;Theis et al, 2021). High TLE1 expression in lung adenocarcinoma is associated with a poor prognosis (Ma et al, 2021) but, surprisingly, is associated with tumor inhibition and a better prognosis in pancreatic cancer (Wang et al, 2020).…”

“…In addition, the expression of inflammatory cytokines was increased in multiple organs in Tle1 −/− mice, leading to an unrestrained systemic inflammatory response, suggesting that TLE1 is a critical regulator of development and inflammation (Ramasamy et al, 2016). TLE2 is reported to play a role in the developing mouse pancreas, but surprisingly, mice with global deletion of the Tle2 gene showed no discernable phenotype (Roth et al, 2010;Theis et al, 2021). Global deficiency of Tle3 caused embryonic death, which was associated with abnormal placental development (Gasperowicz et al, 2013), and tissuespecific genetic depletion demonstrated that TLE3 is required for various biological processes, including bone development (Kokabu et al, 2013), myogenic differentiation (Kokabu et al, 2017), lipid storage and thermogenesis (Pearson et al, 2019).…”