Alternative titles; symbols
HGNC Approved Gene Symbol: NKX6-1
Cytogenetic location: 4q21.23 Genomic coordinates (GRCh38): 4:84,491,985-84,499,292 (from NCBI)
In the pancreas, NKX6.1 is required for the development of beta cells and is a potent bifunctional transcription regulator that binds to AT-rich sequences within the promoter region of target genes (Iype et al., 2004).
Homeobox genes encode a highly conserved DNA-binding domain that plays a role in cell-specific differentiation and development. Inoue et al. (1997) cloned the human NKX6A gene. It encodes a predicted 367-amino acid protein that is 97% identical to the protein product of the previously identified hamster NK homeobox gene, Nkx6.1 (Nkx6A), which is expressed in pancreatic islet beta-cell lines.
Sander et al. (2000) stated that embryonic mouse Nkx6-1 is widely expressed in most progenitor cells within ventral neural tube. Using immunocytochemistry and in situ hybridization, they found that Nkx6-1 was expressed in mouse spinal cord and caudal hindbrain at about embryonic day 8.5 (E8.5). It was expressed throughout the ventral third of the neural tube by E9.5, and expression of Nkx6-1 persisted until at least E12.5. Nkx6-1 was expressed by ventral progenitors that give rise to motor neurons and V2 and V3 interneurons. Nkx6-1 was also expressed in mesodermal cells flanking the ventral spinal cord.
Inoue et al. (1997) found that the coding region of human NKX6.1 is composed of 3 exons and spans approximately 4.8 kb.
Inoue et al. (1997) mapped the NKX6.1 gene to chromosome 4q21.2-q22 by fluorescence in situ hybridization.
Gross (2016) mapped the NKX6-1 gene to chromosome 4q21.23 based on an alignment of the NKX6-1 sequence (GenBank AH007313) with the genomic sequence (GRCh38).
Iype et al. (2004) identified a proximal beta cell-specific enhancer (PBE) element in the NKX6.1 gene that is completely conserved between rat, mouse, and human. The PBE is made up of an AT-containing sequence flanked by GC-rich stretches. Mouse Nkx6.1 robustly activated transcription through direct interaction with the AT-rich sequence in this element. By electrophoretic mobility shift assay, Iype et al. (2004) showed that Nkx6.1 bound the PBE in vitro, and by chromatin immunoprecipitation assay, they showed that Nkx6.1 natively occupied this region in vivo in a mouse beta-cell line. Mirmira et al. (2000) demonstrated that when the enhancer region of target genes (e.g., INS, (176730)) contains isolated or tandem TAAT or ATTA homeodomain binding sites, Nkx6.1 directly binds to DNA and represses transcription through interactions involving its N-terminal domain. By contrast, Iype et al. (2004) showed that when a gene such as Nkx6.1 itself contains an ATTT homeodomain binding site in the proximity of a GC-rich region, Nkx6.1 activates transcription through interactions involving an acidic sequence within its C-terminal domain. Iype et al. (2004) concluded that Nkx6.1 is a bifunctional transcription factor that maintains expression of its own gene during beta-cell differentiation while simultaneously effecting broader gene repression events.
Schisler et al. (2005) found that rat Nkx6.1 suppressed glucagon expression and controlled glucose-stimulated insulin secretion in pancreatic beta cells.
In mature pancreatic beta-cells, Nkx6.1 enhances proliferation, glucose-stimulated insulin secretion, and survival. The nuclear receptors Nr4a1 (139139) and Nr4a3 (600542) are necessary for Nkx6.1-mediated proliferation, and VGF (602186) is required to enhance glucose-stimulated insulin secretion and cellular resistance to apoptotic stimuli. Using rat beta-cell lines, Ray et al. (2016) determined that Nkx6.1-mediated upregulation of Nr4a1, Nr4a3, and VGF is dependent on the transcription factor c-Fos (FOS; 164810), which heterodimerizes with c-Jun (JUN; 165160) to form the activator protein-1 (AP1) complex. c-Fos knockdown impeded Nkx6.1-mediated beta-cell proliferation and insulin secretion.
Sander et al. (2000) obtained Nx6-1 -/- mice at the expected mendelian frequency, but mutants died soon after birth and exhibited movement only upon tactile stimulation. Nkx6-1 -/- spinal cord showed a ventral-to-dorsal switch in the identity of neuronal progenitor cells and a corresponding switch in the identity of the neuronal subtype that emerged from the ventral neural tube. Generation of motor neurons and V2 interneurons was markedly reduced, and there was a ventral expansion in the generation of a more dorsal V1 interneuron subtype. Sander et al. (2000) concluded that NKX6-1 is essential in regional patterning and neuronal fate determination in central nervous system.
Using compound mutant mouse embryos, Vallstedt et al. (2001) found that Nkx6-1 and Nkx6-2 had an equivalent inhibitory influence on generation of V0 spinal cord interneurons. Nkx6-1 and Nkx6-2 also showed additive effects, with higher or lower total Nkx6 content directing progenitors to different interneuron or motor neuron cell fates.
Gross, M. B. Personal Communication. Baltimore, Md. 8/31/2016.
Inoue, H., Rudnick, A., German, M. S., Veile, R., Donis-Keller, H., Permutt, M. A. Isolation, characterization, and chromosomal mapping of the human Nkx6.1 gene (NKX6A), a new pancreatic islet homeobox gene. Genomics 40: 367-370, 1997. [PubMed: 9119408] [Full Text: https://doi.org/10.1006/geno.1996.4568]
Iype, T., Taylor, D. G., Ziesmann, S. M., Garmey, J. C., Watada, H., Mirmira, R. G. The transcriptional repressor Nkx6.1 also functions as a deoxyribonucleic acid context-dependent transcriptional activator during pancreatic beta-cell differentiation: evidence for feedback activation of the nkx6.1 gene by Nkx6.1. Molec. Endocr. 18: 1363-1375, 2004. [PubMed: 15056733] [Full Text: https://doi.org/10.1210/me.2004-0006]
Mirmira, R. G., Watada, H., German, M. S. Beta-cell differentiation factor Nkx6.1 contains distinct DNA binding interference and transcriptional repression domains. J. Biol. Chem. 275: 14743-14751, 2000. [PubMed: 10799563] [Full Text: https://doi.org/10.1074/jbc.275.19.14743]
Ray, J. D., Kener, K. B., Bitner, B. F., Wright, B. J., Ballard, M. S., Barrett, E. J., Hill, J. T., Moss, L. G., Tessem, J. S. Nkx6.1-mediated insulin secretion and beta-cell proliferation is dependent on upregulation of c-Fos. FEBS Lett. 590: 1791-1803, 2016. [PubMed: 27164028] [Full Text: https://doi.org/10.1002/1873-3468.12208]
Sander, M., Paydar, S., Ericson, J., Briscoe, J., Berber, E., German, M., Jessell, T. M., Rubenstein, J. L. R. Ventral neural patterning by Nkx homeobox genes: Nkx6.1 controls somatic motor neuron and ventral interneuron fates. Genes Dev. 14: 2134-2139, 2000. [PubMed: 10970877] [Full Text: https://doi.org/10.1101/gad.820400]
Schisler, J. C., Jensen, P. B., Taylor, D. G., Becker, T. C., Knop, F. K., Takekawa, S., German, M., Weir, G. C., Lu, D., Mirmira, R. G., Newgard, C. B. The Nkx6.1 homeodomain transcription factor suppresses glucagon expression and regulates glucose-stimulated insulin secretion in islet beta cells. Proc. Nat. Acad. Sci. 102: 7297-7302, 2005. [PubMed: 15883383] [Full Text: https://doi.org/10.1073/pnas.0502168102]
Vallstedt, A., Muhr, J., Pattyn, A., Pierani, A., Mendelsohn, M., Sander, M., Jessell, T. M., Ericson, J. Different levels of repressor activity assign redundant and specific roles to Nkx6 genes in motor neuron and interneuron specification. Neuron 31: 743-755, 2001. [PubMed: 11567614] [Full Text: https://doi.org/10.1016/s0896-6273(01)00412-3]