Pax4, short for Paired box 4, is a key transcription factor. It consists of a conserved paired box domain and a homeodomain, and is crucial in the embryonic development of the pancreatic islets of Langerhans. Pax4 plays an essential role in early endocrine progenitor cells, being necessary for cell-fate commitment towards the insulin-secreting β cell lineage [1,3,4].

In animal models, knockout of Pax4 leads to the absence of β cells, accompanied by a significant increase in glucagon-producing α cells, and typically results in lethality within days after birth [1,3]. In humans, mutations in Pax4 that cause impaired function are associated with diabetes pathogenesis. For example, the coding variant (p.Arg192His) in PAX4 is associated with an altered risk for type 2 diabetes (T2D) in East Asian populations. In a human beta cell model, PAX4 knockdown led to impaired insulin secretion, reduced total insulin content, and altered hormone gene expression [2]. Also, a mutation in the PAX4 gene (c.487C>T) can cause maturity-onset diabetes of the young (MODY9) [5].

In conclusion, Pax4 is essential for the development of insulin-secreting β cells. Gene knockout models in animals have clearly demonstrated its critical role in pancreatic islet development. In humans, Pax4 mutations are associated with diabetes, highlighting its importance in understanding diabetes pathogenesis and potentially developing new therapeutic strategies for diabetes treatment [1,2,3,4,5].

References:

1. Ko, Jenna, Fonseca, Vivian A, Wu, Hongju. 2023. Pax4 in Health and Diabetes. In International journal of molecular sciences, 24, . doi:10.3390/ijms24098283. https://pubmed.ncbi.nlm.nih.gov/37175989/

2. Lau, Hwee Hui, Krentz, Nicole A J, Abaitua, Fernando, Gloyn, Anna L, Teo, Adrian Kee Keong. 2023. PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development. In Nature communications, 14, 6119. doi:10.1038/s41467-023-41860-z. https://pubmed.ncbi.nlm.nih.gov/37777536/

3. Napolitano, Tiziana, Avolio, Fabio, Courtney, Monica, Navarro, Sergi, Collombat, Patrick. 2015. Pax4 acts as a key player in pancreas development and plasticity. In Seminars in cell & developmental biology, 44, 107-14. doi:10.1016/j.semcdb.2015.08.013. https://pubmed.ncbi.nlm.nih.gov/26319183/

4. Lorenzo, Petra I, Juárez-Vicente, Francisco, Cobo-Vuilleumier, Nadia, García-Domínguez, Mario, Gauthier, Benoit R. 2017. The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences. In Genes, 8, . doi:10.3390/genes8030101. https://pubmed.ncbi.nlm.nih.gov/28282933/

5. Zhang, Di, Chen, Congli, Yang, Wenli, Ren, Li, Sang, Yanmei. . C.487C>T mutation in PAX4 gene causes MODY9: A case report and literature review. In Medicine, 101, e32461. doi:10.1097/MD.0000000000032461. https://pubmed.ncbi.nlm.nih.gov/36595822/