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T.F. Glis3: a novel critical player in the regulation of pancreatic beta-cell development and insulin gene expression

ABSTRACT: Glis3 mutant mice (Glis3zf/zf) die within the first week after birth due to overt diabetes, evidenced by hyperglycemia and hypoinsulinemia. Histopathological analysis showed that Glis3zf/zf mice develop a pancreatic phenotype with a dramatic loss of beta- (insulin) and delta- (somatostatin) cells contrasting a smaller relative loss of alpha- (glucagon), PP- (pancreatic polypeptide), and epsilon- (ghrelin) cells. Glis3zf/zf mice develop ductal cysts with decreased number of primary cilia, while the acini are not significantly affected. Gene expression profiling by microarray analysis demonstrated that the expression of terminal hormonal genes and several transcription factors important in endocrine development were significantly deregulated in Glis3zf/zf mice. During pancreatic development, Glis3 mRNA expression is induced during the secondary transition, a stage of cell lineage specification and extensive patterning. Changes in pancreatic development of Glis3zf/zf mice are noted during and after this stage. The population of pancreatic progenitors appears not to be greatly affected in Glis3zf/zf mice; however, the number of neurogenin 3 (Ngn3) positive, endocrine progenitors is significantly reduced. Our study indicates that Glis3 plays a key role in cell lineage specification, particularly the development of mature pancreatic beta-cells. In addition, we identified evidence that Glis3 regulates insulin gene expression through two Glis-binding sites in its proximal promoter indicating that Glis3 is a regulator of insulin gene expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE18172 | GEO | 2010/01/01

SECONDARY ACCESSION(S): PRJNA119527

REPOSITORIES: GEO

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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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T.F. Glis3: a novel critical player in the regulation of pancreatic beta-cell development and insulin gene expression

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