Zhx2 maintains islet β-cell mass and function by transcriptionally regulating Pax6

Lu Ding; Yankun Zhang; Yingchun Wang; Yuzhen Wang; Zheng Tong; Pengfei Li; Chaojia Chen; Bo Wang; Xuetian Yue; Chunyang Li; Zhuanchang Wu; Xiaohong Liang; Chunhong Ma; Lifen Gao

doi:10.1016/j.isci.2023.106871

Zhx2 maintains islet β-cell mass and function by transcriptionally regulating Pax6

iScience. 2023 May 13;26(6):106871. doi: 10.1016/j.isci.2023.106871. eCollection 2023 Jun 16.

Authors

Affiliations

¹ Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunity, and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China.
² Department of Endocrinology, Yucheng People's Hospital, Dezhou, Shandong 251200, P. R. China.
³ Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China.
⁴ Key Laboratory for Experimental Teratology of Ministry of Education and Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China.

Abstract

Emerging evidence shows that pancreatic β-cell function and quality are key determinants in the progression of type 2 diabetes (T2D). The transcription factor zinc finger homeobox 2 (Zhx2) is involved in proliferation and development of multiple cells. However, the exact role of Zhx2 in β-cells and T2D remains completely unknown. Here, we report that Zhx2 orchestrates β-cell mass and function by regulating paired box protein pax-6 (Pax6). We found that β-cell-specific knockout Zhx2 (Zhx2BKO) mice showed a decrease in β-cell proliferation and glucose homeostasis. Under prediabetic and diabetic conditions, we discovered glucose intolerance in both Zhx2BKO-HFD mice and Zhx2BKO-db/db mice, with reduced β-cell mass and insulin secretion. Mechanistically, we demonstrated that Zhx2 targeted the Pax6 promoter region (-1740∼-1563; -862∼-559; -251∼+75), enhanced promoter activity. Overall, Zhx2 maintains β-cell function by transcriptionally regulating Pax6, which provides a therapeutic target for diabetes intervention.

Keywords: Endocrinology; Model organism; Molecular biology.