NKX6-2, a transcription factor, is involved in multiple biological processes. It plays a role in cell differentiation, such as in the development of specific cell identities in the pancreas, mid-hindbrain, and spinal locomotor circuits, and is also associated with maintaining normal myelination in the central nervous system [2,3,4].

In pancreatic intraductal papillary mucinous neoplasms (IPMNs), loss of NKX6-2 expression is a consistent feature of IPMN progression. Re-expression of Nkx6-2 in murine IPMN lines recapitulates the gastric transcriptional program and glandular morphology, establishing it as a key determinant of gastric cell identity in low-grade IPMNs [1]. In mice, deficiency of the ortholog of NKX6-2 results in widespread hypomyelination in the brain and optic nerve, as well as poor motor coordination, similar to the human phenotype associated with NKX6-2 mutations [5].

In conclusion, NKX6-2 is crucial for cell identity determination in IPMN pathogenesis and normal myelination and motor function. Mouse models with Nkx6-2 deficiency have been instrumental in revealing its role in IPMN progression and the hypomyelination-related spastic ataxia phenotype in humans.

References:

1. Sans, Marta, Makino, Yuki, Min, Jimin, Guerrero, Paola A, Maitra, Anirban. . Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential. In Cancer discovery, 13, 1844-1861. doi:10.1158/2159-8290.CD-22-1200. https://pubmed.ncbi.nlm.nih.gov/37285225/

2. Chelban, V, Alsagob, M, Kloth, K, Houlden, H, Kaya, N. 2019. Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination. In European journal of neurology, 27, 334-342. doi:10.1111/ene.14082. https://pubmed.ncbi.nlm.nih.gov/31509304/

3. Ma, Pengcheng, Xia, Yingjie, Ma, Li, Zhao, Shuhua, Mao, Bingyu. 2013. Xenopus Nkx6.1 and Nkx6.2 are required for mid-hindbrain boundary development. In Development genes and evolution, 223, 253-9. doi:10.1007/s00427-013-0437-9. https://pubmed.ncbi.nlm.nih.gov/23423436/

4. Toch, Mathilde, Harris, Audrey, Schakman, Olivier, Tissir, Fadel, Clotman, Frédéric. 2020. Onecut-dependent Nkx6.2 transcription factor expression is required for proper formation and activity of spinal locomotor circuits. In Scientific reports, 10, 996. doi:10.1038/s41598-020-57945-4. https://pubmed.ncbi.nlm.nih.gov/31969659/

5. Chelban, Viorica, Patel, Nisha, Vandrovcova, Jana, Alkuraya, Fowzan S, Houlden, Henry. . Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination. In American journal of human genetics, 100, 969-977. doi:10.1016/j.ajhg.2017.05.009. https://pubmed.ncbi.nlm.nih.gov/28575651/