Defining a Novel Role for the Pdx1 Transcription Factor in Islet β-Cell Maturation and Proliferation During Weaning

Abstract

The transcription factor encoded by the Pdx1 gene is a critical transcriptional regulator, as it has fundamental actions in the formation of all pancreatic cell types, islet β-cell development, and adult islet β-cell function. Transgenic- and cell line–based experiments have identified 5′-flanking conserved sequences that control pancreatic and β-cell type–specific transcription, which are found within areas I (bp −2694 to −2561), II (bp −2139 to −1958), III (bp −1879 to −1799), and IV (bp −6200 to −5670). Because of the presence in area IV of binding sites for transcription factors associated with pancreas development and islet cell function, we analyzed how an endogenous deletion mutant affected Pdx1 expression embryonically and postnatally. The most striking result was observed in male Pdx1ΔIV mutant mice after 3 weeks of birth (i.e., the onset of weaning), with only a small effect on pancreas organogenesis and no deficiencies in their female counterparts. Compromised Pdx1 mRNA and protein levels in weaned male mutant β-cells were tightly linked with hyperglycemia, decreased β-cell proliferation, reduced β-cell area, and altered expression of Pdx1-bound genes that are important in β-cell replication, endoplasmic reticulum function, and mitochondrial activity. We discuss the impact of these novel findings to Pdx1 gene regulation and islet β-cell maturation postnatally.

Islet Gene View - a tool to facilitate islet research

“…The explanation for these somewhat disparate findings is unclear but could involve a compensatory response from the beta cell to slow down repolarization. Figure 6) encodes another transcription factor that is required for beta-cell maturation and maintenance (Spaeth et al, 2017). We here add new information showing that PDX1 is downregulated in T2D supporting previous findings that its expression correlates with chronic hyperglycemia (Fujimoto and Polonsky, 2009) .…”

SIRT5 regulates pancreatic β‑cell proliferation and insulin secretion in type 2 diabetes

“…Moreover, β cell-specific inactivation of Pdx1 in the adult mouse causes severe hyperglycemia and loss of cell identity, with these cells transdifferentiating to an islet α-like cell capable of secreting the glucagon hormone (18). Previous studies have demonstrated that PDX1 serves a primary role in diabetes and that the downregulation of PDX1 expression aggravates diabetes mellitus (29,30). The results of the present study demonstrated that SIRT5 may regulate the transcription of PDX1 through its deacetylase activity.…”

NSD2 is downregulated in T2DM and promotes β cell proliferation and insulin secretion through the transcriptionally regulation of PDX1

“…PDX1 has been reported to play fundamental roles in diabetes mellitus, abnormal expression of PDX1 suppressed pancreatic β cell proliferation (32,33). NSD2 as transcription factor, we assumed NSD2 might transcriptionally regulated PDX1 in pancreatic β cell lines.…”