Nkx2-2, a homeodomain transcription factor, is crucial in the development of multiple organs. It is a key effector molecule positively regulated by the Sonic hedgehog (Shh) pathway, which is vital for central nervous system (CNS) patterning, growth, development, and tumorigenesis [1]. Nkx2-2 is essential for V3 domain specification during neural tube patterning in the embryonic stage and for the later stage of oligodendrocyte maturation in the CNS [1]. It also governs cell fate decisions in the pancreas, intestine, and taste system [2,3,4,6]. Genetic models, such as gene knockout (KO) mouse models, have been valuable in studying its functions.

In Nkx2-2 knockout mice, severe neonatal diabetes occurs, along with changes in β -cell progenitor fate into ghrelin-producing cells, which is recapitulated in human patients with recessive NKX2-2 gene mutations presenting with neonatal diabetes, severe obesity, and developmental delay [7]. Neonatal Nkx2-2-knockout mice do not express key type III taste cell marker genes, indicating Nkx2-2 is critical for the development of type III taste cells in the posterior tongue [3]. In addition, overexpression of NKX2-2 in osteosarcoma cells decreases their migration, invasion, proliferation, and colony formation in vitro and suppresses tumor growth and metastasis in vivo, suggesting it acts as a tumor suppressor for osteosarcoma [5].

In conclusion, Nkx2-2 plays essential roles in organ development, cell fate determination, and metabolism. Studies using KO mouse models have revealed its significance in diseases like neonatal diabetes, obesity, and osteosarcoma. Understanding Nkx2-2 provides insights into normal biological processes and disease mechanisms, potentially leading to new therapeutic strategies for related conditions.