Hes3 Is Expressed in the Adult Pancreatic Islet and Regulates Gene Expression, Cell Growth, and Insulin Release

Abstract

Background:The transcription factor Hes3 regulates the growth of neural and brain cancer stem cells. Results: Hes3 regulates growth, gene expression, evoked insulin release in cultured insulinoma cells, and sensitivity to streptozotocin in vivo. Conclusion: Hes3 is a novel regulator of cellular functions of importance in diabetes. Significance: Introducing Hes3 and its regulators in diabetes research may provide new opportunities for the design of novel therapeutics.

Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

“…Early data from mice lacking Hes3 corroborate some of these ideas because these mice exhibit phenotypes of direct relevance to pancreatic function; specifically, whereas otherwise apparently normal, these mice exhibit a more pronounced loss of pancreatic b-cells, develop diabetes faster (43), and show impaired regeneration (as assessed by b-cell marker expression) after streptozotocin (STZ)-induced pancreatic damage (Fig. 3B-D).…”

“…Early reports demonstrated the operation of the STAT3-Ser/Hes3 signaling axis in adult pancreatic cells in vitro and in vivo (43). It may be worth speculating how this pathway may intercept other established signaling pathways involved in pancreas development and function, including the mitogenic FGF pathway, Notch (canonical via Hes1, noncanonical via Hes3), and the hedgehog pathway.…”

“…Hes6 may also play a role in inhibiting Hes1 in this system. studies have been performed, although in the adult Hes3-null mouse, no gross morphological phenotypes are obvious (43,88). Perhaps, this mechanism is particularly active during regeneration because Hes3-null mice exhibit increased damage and reduced regeneration of b-cells after STZ damage (43).…”

“…D: Examples of islets after the experimental procedure described in C. Experimental details for panels B-D: low-dose STZ treatment was performed as previously described (43), but the mice were allowed to survive for 5 months after the last injection (n = 6 mice per each of the 4 groups). Immunolabeling images were acquired after 4% paraformaldehyde fixation and sectioning; counting was from 30 islet sections per group.…”

“…A cell that is exhibiting low activity of a canonical pathway may actually also exhibit high activity in noncanonical pathways that are only now becoming revealed. For example, whereas canonical Notch (caNotch) signaling is often assessed by the amount of Hes1 expression (a caNotch pathway target gene), it is possible that the cell exhibits high expression of, for example, Hes3, an indirect, noncanonical target of Notch (noncaNotch) with distinct outcomes in NSCs (43). Low activity of a signaling pathway, as assessed by measurements of its canonical functions, does not preclude that other branches of the same pathway are not highly active.…”