Trends in Endocrinology & Metabolism
ReviewMafA and MafB activity in pancreatic β cells
Section snippets
β Cell generation as a source of replacement therapy for diabetes mellitus
Pancreatic islet β cells are the only cell type in the body to secrete the hormone insulin in response to glucose. High levels of glucose stimulate insulin secretion from β cells. This hormone first acts on liver to increase glycogen synthesis and inhibit gluconeogenesis. Subsequently, insulin promotes glucose uptake and storage in skeletal muscle and adipose tissue. In addition to increased blood glucose concentrations, insulin is also secreted in response to amino acids, free fatty acids,
MafA and MafB are the principal large Maf transcription factors in the pancreas
The family of large Maf proteins is composed of four distinct genes/proteins (Box 1), MafA, MafB, c-Maf and Nrl, which all contain N-terminal transactivation and C-terminal basic leucine-zipper DNA-binding domains. The in vitro DNA-binding properties of MafA, MafB, and c-Maf are indistinguishable [23]. c-Maf has been reported to be expressed in the pancreas 20, 24, 25, 26, whereas pancreatic Nrl expression is undetectable [27]. Significantly, pancreas development is unaffected in c-Maf null
MafA and MafB have unusual expression patterns during islet cell development
MafA and MafB are expressed in a unique temporospatially regulated manner in relation to other islet-enriched factors in developing and postnatal murine islet cells. MafB is expressed earlier than MafA, with initial production being detected around embryonic (E) day E10.5 in the pancreatic epithelium 20, 25. By contrast, MafA is first produced at E13.5 and only in insulin+ cells [43]. Their developmental expression patterns are also unusually late in comparison to all other islet-enriched
Only MafB is required during mouse β cell development.
The pancreatic transcription factors play important roles in pancreas development (Figure 2). Almost all these transcription factor knockout mice result in either the loss in hormone+ cell numbers and/or respecification to another islet cell type 47, 48, 49, 52. For instance, Pdx1 is crucial for pancreas outgrowth during development, with loss leading to pancreas agenesis in mice and humans 52, 53, 54. This condition results in death soon after birth unless treated for the loss of
The potential role of MafA and MafB in islet β cell generation from non-β cells
In view of the significance of MafA in glucose-responsive transcription and adult β function, MafA has been used to induce β cell differentiation in both human and rodent stem cells and differentiated cell types (Table 1). The MafA protein, alone or in combination with other pancreatic transcription factors, was able to induce the expression of insulin and other key β cell markers. In most cases the generated insulin+ cells improved blood glucose levels in streptozotocin-induced diabetic
Concluding remarks
Studies on MafA and MafB using mouse models have revealed their crucial roles in islet β cell formation and function, with MafB being required during development and MafA in adults. Gene-expression analyses disclosed that the two closely related transcription factors regulate key β cell genes in a cooperative and sequential manner. Research both in mouse models and in hES cell differentiation in vitro showed that the switch from MafB+ to MafA+ is vital for functional maturation of β cells.
Acknowledgments
R.S. is supported by grants from the National Institutes of Health (DK050203, DK077971, and DK089572).
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