The human NKX2-3 gene has two transcripts. NKX2-3-001, ENST00000344586, 2097 nt mRNA encoding a protein of 364 amino acids; NKX2-3-201, ENST00000622383, 1986 nt mRNA encoding a protein of 296 amino acids.

The gene has two exons and one intron.

The transcription takes place in a centromere --> telomere orientation. The length of the processed mRNA is about 2094 nucleotides.

Not known.

The NKX2-3 protein is a 364-amino acid (molecular weight 38405.63g/mol) protein.

The NKX2-3 protein (364 amino acids) translated from the long transcript contains a TN domain (residues 10-19), HD domain (residues 148-207), SD domain (residues 222-238) and TAD domain (residues 239-364).

Expression is mainly observed in pharynx, small intestine, liver, spleen, heart, lymph node, thyroid, adrenal gland, breast, skin, ovary, prostate, testis, and retina.

Nucleus, but also observed outside the nucleus.

NKX2-3 is a nuclear transcription factor that plays an important role in the regulation of gene transcription. Studies from siRNA knockdown followed by cDNA profiling indicate that many genes are regulated by NKX2-3. This indicates involvement of NKX2-3 in the regulation of transcription, of immune and inflammatory response, cell growth and proliferation, cell adhesion, metabolic processes, angiogenesis, lymph-angiogenesis, and others (Yu et al., 2011).
Results from NKX2-3 deficient mice and other studies demonstrate that NKX2-3 is essential for intestine and spleen development (Pabst et al., 1999; Pabst et al., 2000). NKX2-3 is required for heart formation (Fu et al., 1998) and salivary gland and tooth morphogenesis and plays a role during pharyngeal organogenesis (Biben et al., 2002). NKX2-3 is essential for B cell maturation and T cell dependent immune response (Shaffer et al., 2013), and regulates leukocyte homing through local control of cellular adhesion molecules including MADCAM-1 and VCAM in mice (Wang et al., 2000) and IBD patients (our unpublished data).
Nkx2-3 and regulation of the arteriovenous endothelial profile
Individual transcription factors interact in a complex network to regulate the arteriovenous profile. Aranguren et al. 2013 examined the expression of 64 known arterial and 12 known venous genes from freshly isolated arterial and venous endothelial cells from human umbilical cord. The expression of approximately 36% of the examined arterial genes was found to be regulated by NKX2-3 (Aranguren et al., 2013).
Nkx2-3 and lymphoid tissue development
It remains to be determined whether the formation of enteric lymphatic capillaries is affected by the absence of Nkx2-3, similar to the observed reduction of Peyers patches. In contrast to the leukocyte homing in pLNs and Peyers patches, the spleen lacks high endothelial venules (HEVs) and requires no L-selectin binding for subsequent leukocyte extravasation. Evidence indicated that the integrity of the marginal sinus and the proper vascular segregation of the red pulp was controlled by NKX2-3 (Balogh et al., 2007).
Czömpöly et al. 2011 found that the disruption of Nkx2-3 expression in mice, the spleen develops a peripheral lymph node (pLN)-like mRNA expression signature, coupled with the appearance of HEVs. These HEV-like vessels undergo postnatal maturation and progressively replace MAdCAM-1 by pLN addressin together with the display of CCL21 arrest chemokine, reminiscent of HEV formation in pLNs (Czömpöly et al., 2011). This transformation of splenic vasculature into pLN-like vessels emphasizes the importance of Nkx2-3 in correct vessel formation for spleen ontogeny in mammals.
Kellermayer et al. 2011 reported that Nkx2.3-deficient mice develop splenic and gut-associated vascular and lymphoid tissue abnormalities with disordered segregation of T- and B- cells. Splenic defects include absence of the marginal sinus vasculature and an atrophic red pulp sinus network with an extensive network of lymphocyte-filled endothelial sacs lined by cells expressing LYVE-1, a marker associated with lymphatic endothelium cells (Kellermayer et al., 2011). This raises the possibility that endothelial differentiation and maturation may be affected by altered expression of Nkx2-3.

NKX2-3 is a homeodomain protein belonging to the NK2 family. The other NK2 family members are Nkx2-1 (at 14q13), Nkx2-2 (at 20p11), Nkx2-3 (at 10q24.2), Nkx2-4 (at 20p11), Nkx2-5, Nkx2-6, Nkx2-8, Nkx2-9 (at 14q13), and Nkx2-10.
Orthologs of NKX2-3 show a high similarity with the homologues in other species, such as 88.46% (nt) and 90.86% (aa) with mouse, 60% (aa) with chicken, 79% (nt) with Xenopus laevis, 76.29% (nt) with zebrafish, 20% (aa) with fruit fly, and 33% (aa) with worm.

A total of 304 genetic variants are documented, including 128 upstream and 87 downstream of the gene, 5 variants in the 5 prime and 15 in the 3 primer untranslated regions, 26 missense and 17 synonymous variants in exons, 23 variants in introns, and 2 in-frame deletions.

A total of 13 somatic mutations have been reported: one is a 21 bp deletion, two are synonymous variants, and 10 missense variants.
Histological examination showed all the mutations are observed in carcinoma.

A ETV6-GOT1 fusion contains a chimeric transcript containing ETV6 sequence fused to genomic sequences located at 22961 bp 3 to GOT1 and 79407 bp 5 to NK2 transcription factor related, locus 3 (NKX2-3). This may result in the dysregulation of NKX2-3, which lies adjacent to the breakpoint (Struski et al., 2008).