Group Leader / Reader in Stem Cell Biology King's College London (KCL) King's College London, England, United Kingdom
Abstract: The differentiation of insulin-producing beta cells relies on precise regulatory mechanisms that govern cell fate decisions. Neurogenin 3 (Neurog3), a transcription factor essential for endocrine lineage specification, plays a critical role in this process. However, the mechanisms that regulate Neurog3 activity and stability remain incompletely understood. Our study identifies the lysosome as a key regulator of Neurog3 protein stability, providing a new layer of control over pancreatic endocrine differentiation. Using iPSC-derived pancreatic organoids, we have characterised a regulatory network through which lysosomal pathways influence the temporal dynamics of Neurog3 activity, directing progenitors towards beta cell fate. These findings provide insight into how lysosomal function contributes to pancreatic development and how disruptions in this pathway may contribute to disease. This work highlights the lysosome as a central player in transcription factor regulation and its potential as a target for improving beta cell differentiation. By linking lysosomal regulation to endocrine lineage decisions, this research advances our understanding of pancreatic biology and its implications for developing therapies for diabetes.
Funding Source: This work was supported by Wellcome Trust (207529/Z/17/Z), MRC (MR/S000011/1) and MRC/JDRF (MR/T015470/1) to R.S. A.G was funded by the Wellcome Trust (207529/Z/17/Z). T.M was supported by a Wellcome Trust (215138/Z/18/Z).
