Pax4-Ghrelin mediates the conversion of pancreatic ε-cells to β-cells after extreme β-cell loss in zebrafish

• Published in: Development (Cambridge) Vol. 150; no. 6
• Main Authors: Yu, Junqin, Ma, Jianlong, Li, Yanfeng, Zhou, Yang, Luo, Lingfei, Yang, Yun
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 15-03-2023
• Subjects: Animals; Ghrelin - metabolism; Homeodomain Proteins - metabolism; Pancreas; Stem Cells and Regeneration; Transcription Factors - metabolism; Zebrafish - genetics; Zebrafish - metabolism; Pax4; Zebrafish; Ghrelin; β-cell regeneration; ε-cell transdifferentiation
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.201306

Pancreatic ε-cells producing ghrelin are one type of endocrine cell found in islets, which have been shown to influence other intra-islet cells, especially in regulating the function of β cells. However, the role of such cells during β-cell regeneration is currently unknown. Here, using a zebrafish nitroreductase (NTR)-mediated β-cell ablation model, we reveal that ghrelin-positive ε-cells in the pancreas act as contributors to neogenic β-cells after extreme β-cell loss. Further studies show that the overexpression of ghrelin or the expansion of ε-cells potentiates β-cell regeneration. Lineage tracing confirms that a proportion of embryonic ε-cells can transdifferentiate to β-cells, and that the deletion of Pax4 enhances this transdifferentiation of ε-cells to β-cells. Mechanistically, Pax4 binds to the ghrelin regulatory region and represses its transcription. Thus, deletion of Pax4 derepresses ghrelin expression and causes producing more ghrelin-positive cells, enhancing the transdifferentiation of ε-cells to β-cells and consequently potentiating β-cell regeneration. Our findings reveal a previously unreported role for ε-cells during zebrafish β-cell regeneration, indicating that Pax4 regulates ghrelin transcription and mediates the conversion of embryonic ε-cells to β-cells after extreme β-cell loss.