Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression profiling of MafA, MafB, and MafA/MafB Mutants in E18.5 pancreas

ABSTRACT: MafA and MafB transcription factors have been shown to be key regulators of insulin and glucagon transcription. MafB is essential for alpha and beta cell differentiation, as MafB deficient mice produced fewer insulin+ and glucagon+ cells during development, with MafA expressed in remaining insulin+ cells. In contrast, beta cell development was reported to be normal in a total MafA knock out, although the animals developed beta cell dysfunction and diabetes as adults. However, we have found that MafB expression is elevated during development and retained in adult insulin+ cells after conditional removal of MafA in the pancreas. These studies will evaluate the broader significance of these insulin and glucagon regulators in alpha and beta cell development and function. Our efforts will focus on determining if the concerted actions of MafA and MafB factors are significant to beta cell formation, and we specifically plan to: Determine how alpha and beta cell differentiation is affected in MafA/MafB compound mutant mice during pancreas development. cDNA microarray studies (pancchip 6.0) with wild type, MafAKO, MafB-/-, and MafAKOMafB-/- mutant E18.5 pancreata will be performed to comprehensively identify genes controlled by MafA and MafB in developing alpha and beta cells.

INSTRUMENT(S): Agilent DNA Microarray Scanner Model #G2565BA

ORGANISM(S): Mus musculus

SUBMITTER: Roland Stein

PROVIDER: E-MTAB-3070 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Pancreatic Beta-cells are essential for regulating blood glucose levels. Much of our knowledge relating to human Beta-cell development and function has depended on rodent models, which have provided a blueprint to confirm important cellular features in humans. The advent of next generation sequencing studies, however, has highlighted discrepancies in Beta-cells which exist between mice and men. The precise contribution of such differences has not yet been fully appreciated. Numerous studies have identified MAFB to be present in human Beta-cells postnatally, while its expression is restricted to embryonic and neo-natal Beta-cells in mice. Conversely, the related transcription factor MAFA is only active in mature murine Beta-cells and notably, knockout of MAFB has minimal effect on murine Beta-cell development and function, in contrast to MAFA. Using CRISPR/Cas9-mediated gene editing, coupled with endocrine cell differentiation strategies, we dissect the contribution of MAFB to Beta-cell development and function specifically in humans. MAFB knockout hPSCs have normal pancreatic differentiation capacity up to the progenitor stage, but favor somatostatin- and pancreatic polypeptide–positive cells at the expense of insulin- and glucagon-producing cells during endocrine cell specification. Our results uncover a requirement for MAFB late in the human pancreatic developmental program and identify it as a distinguishing transcription factor within islet cell subtype specification. Taken together, the current study demonstrates that MAFB has synonymous functions in mice and human Alfa and Beta-cell specification and uncovers previously unappreciated roles in other pancreatic endocrine cell types, in particular Gamma-cells. We propose that under-appreciated differences in rodent versus human pancreatic islet biology may be alleviated by expanding genetic observations in animal models by utilizing hPSCs to better model human Beta-cell development and associated disease pathophysiology such as diabetes.

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Gene expression profiling of MafA, MafB, and MafA/MafB Mutants in E18.5 pancreas

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