The Krüppel-like zinc finger transcription factor GLIS3 has been identified as a critical regulator of pancreatic beta cell development and function. Mice lacking a functional Glis3 gene fail to produce enough insulin and suffer from severe hyperglycemia soon after birth. This phenotype matches what has been observed in humans with genetic mutations in GLIS3 and who have been diagnosed with permanent neonatal diabetes within the first month of life. Additional and ongoing work has begun to identify some of the transcriptional mechanisms utilized by GLIS3, yet many questions remain unanswered.

One such question is whether GLIS3 has roles in endocrine development prior to the formation of functional β-cells. To address this question, I have utilized single cell RNA-sequencing of mouse embryonic pancreas, at embryonic days (e)15.5 and e18.5, of both wild type (WT) and Glis3 knockout (KO) embryos. Analysis of this data has identified the expected developmental populations, from bipotent progenitor cells to pro-endocrine cells and ultimately hormone positive β-, α-, δ-, and ε-cells. Interestingly, there is little difference in gene expression between the WT and Glis3 KO pancreas in most of the populations observed (pro-endocrine, FEV+, α-/δ-/ε-cells). However, there are significant differences in gene expression between WT β-cells and KO β-cells. Surprisingly, most of the differences are in genes upregulated in the KO cells, with only a small number of genes downregulated. These upregulated genes are normally downregulated over the course of development from FEV+ to β-cells. These data indicate that GLIS3 plays a unique role in developing β-cells in that it primarily represses genes during the course of development but is also critical for the transcriptional activation of specific targets, particularly Ins2. Understanding how GLIS3 regulates β-cell generation, and how GLIS3 itself is regulated, could potentially provide new therapeutic avenues for the treatment of diabetes.


D. W. Scoville: None. S. Grimm: None. A. M. Jetten: None.


National Institutes of Health (Z01-ES-101585)

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