The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis

Abstract

The orphan nuclear receptor NR5A2 is necessary for the stem-like properties of the epiblast of the pre-gastrulation embryo and for cellular and physiological homeostasis of endoderm-derived organs postnatally. Using conditional gene inactivation, we show that Nr5a2 also plays crucial regulatory roles during organogenesis. During the formation of the pancreas, Nr5a2 is necessary for the expansion of the nascent pancreatic epithelium, for the subsequent formation of the multipotent progenitor cell (MPC) population that gives rise to pre-acinar cells and bipotent cells with ductal and islet endocrine potential, and for the formation and differentiation of acinar cells. At birth, the NR5A2-deficient pancreas has defects in all three epithelial tissues: a partial loss of endocrine cells, a disrupted ductal tree and a >90% deficit of acini. The acinar defects are due to a combination of fewer MPCs, deficient allocation of those MPCs to pre-acinar fate, disruption of acinar morphogenesis and incomplete acinar cell differentiation. NR5A2 controls these developmental processes directly as well as through regulatory interactions with other pancreatic transcriptional regulators, including PTF1A, MYC, GATA4, FOXA2, RBPJL and MIST1 (BHLHA15). In particular, Nr5a2 and Ptf1a establish mutually reinforcing regulatory interactions and collaborate to control developmentally regulated pancreatic genes by binding to shared transcriptional regulatory regions. At the final stage of acinar cell development, the absence of NR5A2 affects the expression of Ptf1a and its acinar specific partner Rbpjl, so that the few acinar cells that form do not complete differentiation. Nr5a2 controls several temporally distinct stages of pancreatic development that involve regulatory mechanisms relevant to pancreatic oncogenesis and the maintenance of the exocrine phenotype.

Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

“…214 Nuclear receptor subfamily 5 group A member 2 (NR5A2) is a member of the nuclear hormone receptor family and has been identified as a regulator of pancreatic organogenesis. 215 NR5A2 is required for the expansion of the nascent pancreatic epithelium and subsequently in the genesis of MPCs. NR5A2 deficient mice display impairment in all 3 pancreatic epithelial tissue types evident by partial loss of endocrine cells, >90% deficit of acinar cells and a disrupted ductal tree.…”

“…NR5A2 deficient mice display impairment in all 3 pancreatic epithelial tissue types evident by partial loss of endocrine cells, >90% deficit of acinar cells and a disrupted ductal tree. 215 Additionally, NR5A2, Ptf1a and Rbpjl control additional regulatory genes including Foxa2, Gata4 and myelocytomatosis oncogene (MYC). 215 The novel transcription factors, Ets variant 1 (Etv1), PR domain containing 16 (Prdm16), runt-related transcription factor 1 translocated to 1 (Runx1t1) and B-cell lymphoma/leukemia 11A (Bcl11a) were identified as regulators of pancreas organogenesis.…”

“…215 Additionally, NR5A2, Ptf1a and Rbpjl control additional regulatory genes including Foxa2, Gata4 and myelocytomatosis oncogene (MYC). 215 The novel transcription factors, Ets variant 1 (Etv1), PR domain containing 16 (Prdm16), runt-related transcription factor 1 translocated to 1 (Runx1t1) and B-cell lymphoma/leukemia 11A (Bcl11a) were identified as regulators of pancreas organogenesis. 216 The R spondin receptor, Lgr5, is implicated with an organoid-forming epithelial progenitor population, but little is known about this organoid-initiating epithelial progenitor population.…”

Transcriptional regulation by NR5A2 couples cell differentiation and inflammation in the pancreas

“…The current notion is that the control of inflammatory responses relies on transcriptional networks distinct from those involved in cell differentiation 2,3 . The orphan nuclear receptor NR5A2 (also known as LRH-1) participates in a wide variety of processes including cholesterol and glucose metabolism in the liver, resolution of ER stress, intestinal glucocorticoid production, pancreatic development, and acinar differentiation [4][5][6][7][8] . In mice, Nr5a2 deletion leads to variable degrees of pancreatic hypoplasia depending on the timing of its inactivation 6,8 .…”

“…The orphan nuclear receptor NR5A2 (also known as LRH-1) participates in a wide variety of processes including cholesterol and glucose metabolism in the liver, resolution of ER stress, intestinal glucocorticoid production, pancreatic development, and acinar differentiation [4][5][6][7][8] . In mice, Nr5a2 deletion leads to variable degrees of pancreatic hypoplasia depending on the timing of its inactivation 6,8 . By contrast, constitutive Nr5a2 heterozygosity allows normal pancreatic development but is associated with impaired regeneration upon induction of mild acute inflammation and sensitizes pancreatic epithelial cells to mutant KRas-driven preneoplastic lesions and pancreatic ductal adenocarcinoma (PDAC) 9 .…”