Dissecting the role of Neurogenin3 in delta cell development and beta cell regeneration.

Restoring the functional β-cell mass is a promising approach to reinstating automated glucose control
in type 1 diabetes. However, β-cell transplantation alone is not considered true regeneration since it
does not repair the damaged endocrine pancreas. Therefore, our research focuses on in situ β-cell
regeneration and specifically on understanding the role of the basic helix-loop-helix transcription
factor Neurogenin3 (Neurog3). Neurog3 is crucial in endocrine pancreas development, but its
function in differentiated endocrine cells is unclear. We recently discovered that Neurog3 expression
in the adult pancreas is confined to the somatostatin-producing ∂-cells, which is significant because
Neurog3 is critical to adult β-cell regeneration. Our collaborators also identified ERBB4, a
determinant of ∂-cell fate, as a Neurog3-target in human stem cell-derived endocrine progenitors.
We aim to understand better Neurog3's role in adult ∂-cells and its potential to drive β-cell
regeneration. We hypothesize that low levels of Neurog3 maintain ∂-cell identity, and transient
upregulation enables ∂-to-β-cell conversion. To unravel the role of Neurog3 in ∂-cells during
homeostasis and diabetes, we plan to use targeted DamID and gain and loss of function studies in
mice and human stem cells. Ultimately, our goal is to contribute to developing a Neurog3-based
regenerative therapy for diabetes.