Nkx2-3, a member of the NK-class Nkx paralogues, is a homeobox transcription factor involved in multiple biological processes. It plays key roles in the development of lymphoid tissues, hematopoiesis, and the formation of certain cartilages. It is also associated with pathways like mitophagy, Fgf signaling, and the AMPK/mTOR signaling pathway, and is important in maintaining the self-renewal of hematopoietic stem cells and determining cell identities in salivary glands [1-4]. Genetic models, especially knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its functions.

In mice with conditional deletion of Nkx2-3, the HSC pool and long-term repopulating capacity are reduced, and HSC quiescence is impaired, highlighting its role in HSC self-renewal [1]. Knockdown or knockout of nkx2.3 in zebrafish leads to the absence of posterior ceratobranchial cartilages due to compromised cranial neural crest cell proliferation, differentiation, and survival, with nkx2.3 negatively regulating Fgf signaling [2]. Disruption of the Nkx2-3 gene in mice delays the maturation of sublingual gland mucous acinar cells, suggesting its role in specifying mucous cell identity [3]. In mice lacking Nkx2-3, ectopic lymphatic endothelial differentiation occurs in the spleen, accompanied by impaired extramedullary stress hematopoiesis [4].

In conclusion, Nkx2-3 is crucial for the development of various tissues and organs, and its regulation of cell-specific functions. Studies using KO/CKO mouse models have provided insights into its role in hematopoietic malignancies, gut inflammation, and other disease-related conditions, facilitating a better understanding of the underlying molecular mechanisms and potentially paving the way for new therapeutic strategies.