MafB Is Critical for Glucagon Production and Secretion in Mouse Pancreatic α Cells In Vivo

Abstract

The MafB transcription factor is expressed in pancreatic α and β cells during development but becomes exclusive to α cells in adult rodents. -null ( ) mice were reported to have reduced α- and β-cell numbers throughout embryonic development. To further analyze the postnatal function of MafB in the pancreas, we generated endocrine cell-specific ( ) and tamoxifen-dependent ( ) knockout mice. mice exhibited reduced populations of insulin-positive (insulin) and glucagon cells at postnatal day 0, but the insulin cell population recovered by 8 weeks of age. In contrast, the Arx glucagon cell fraction and glucagon expression remained decreased even in adulthood. mice, with deleted after pancreas maturation, also demonstrated diminished glucagon cells and glucagon content without affecting β cells. A decreased Arx glucagon cell population in mice was compensated for by an increased Arx pancreatic polypeptide cell population. Furthermore, gene expression analyses from both and islets revealed that MafB is a key regulator of glucagon expression in α cells. Finally, both mutants failed to respond to arginine, likely due to impaired arginine transporter gene expression and glucagon production ability. Taken together, our findings reveal that MafB is critical for the functional maintenance of mouse α cells , including glucagon production and secretion, as well as in development.

Fast, sensitive, and accurate integration of single cell data with Harmony

“…This cluster was also enriched with genes involved in ER stress ( Figure 5J , DDIT3 , ATF3 , ATF4 , and HSPA5 ). Similar to the beta ER stress population, these alpha cells also expressed significantly lower levels of genes necessary for proper function: 20, 21 GCG , ISL1 , ARX , and MAFB ( Figure 5K ). A recent study 22 reported ER stress in alpha cells in mice and linked the stress to dysfunctional glucagon secretion.…”

Role of MafB in macrophages

“…Given these findings, we identified the direct target genes of MafB, including F4/80, AIM, C1qa, C1qb, C1qc, and MSR1, by using Mafb f/f: :LysM-Cre mice ( helper cells, and rhodopsin in rod cells [30,33,34,38,49,82]. Consequently, if the target genes of MafB in macrophages are found, the unknown functions of macrophages can be clarified.…”

“…For instance, c-Maf regulates the interleukin (IL) 4 (IL4) gene in helper T cells, the IL10 gene in macrophages, and crystallin genes in lens fiber cells [7,34,38]. MafB also regulates glucagon gene expression in pancreatic α cells, the PTH gene in the parathyroid gland, and C1q genes in macrophages [30,33,74]. Thus, this indicates that large Mafs regulate critical genes that define their cell types.…”

Uncovering the role of MAFB in glucagon production and secretion in pancreatic α-cells using a new α-cell-specific <i>Mafb</i> conditional knockout mouse model

“…Cell counting was performed as previously described [26]. Briefly, tdsRed-positive, glucagon-positive; td-sRed-positive, glucagon-negative; insulin-positive; glucagon-positive; aRX-positive; and glucagon-positive, aRX-positive cells in each islet were counted manually in the microscopy images taken as described in the immunohistochemical staining section.…”

“…Mafb binds to the g1 element of the Gcg promoter together with other transcription factors, activating transcription of the Gcg gene and conferring α-cell specificity [4]. Recently, our laboratory demonstrated that Mafb is essential for glucagon production and secretion in mouse pancreatic α-cells after birth by using endocrine cellspecific Mafb-deficient models, Mafb f/f ::Ngn3-Cre (Mafb ΔEndo ) and Mafb f/f ::CAGG-CreER (Mafb ΔTAM ) mouse models [26]. However, using a pancreatic-specific Mafb conditional knockout (Mafb f/f ::Pdx1-Cre, Mafb Δpanc ) mouse model, Conrad et al reported a resto-ration of glucagon-positive α-cell count and islet glucagon content by 2 weeks and 8 weeks of age, respectively [12].…”