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Gene Review

Nkx2-2  -  NK2 homeobox 2

Mus musculus

Synonyms: Homeobox protein NK-2 homolog B, Homeobox protein Nkx-2.2, Nkx-2.2, Nkx2.2, Nkx2b, ...
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Disease relevance of Nkx2-2

  • In addition, we show that mice homozygous for a null mutation of Nkx2.2 develop severe hyperglycemia and die shortly after birth [1].

High impact information on Nkx2-2


Biological context of Nkx2-2


Anatomical context of Nkx2-2

  • Remarkably, Nkx2-2 is ectopically activated in the sclerotome and limb buds of Pax1(Un-s) embryos, both of which normally express Pax1 [10].
  • The region where the astrocyte-specific glutamate transporter is strongly expressed in the ventral radial glial cells is closely related to the Pax6-expressing domain, and the weakly expressing region corresponding to the Nkx2.2-expressing domain [11].
  • Regional expression of the homeobox gene Nkx-2.2 in the developing mammalian forebrain [4].
  • Within the pancreatic islet, the homeodomain protein Nkx2.2 is essential for the differentiation of all insulin-producing beta cells and a subset of glucagon-producing alpha cells (1) [12].
  • Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain transcription factor [13].

Physical interactions of Nkx2-2

  • In developing neural tube, the basic helix-loop-helix (bHLH) transcription factor Olig2 interacts with the homeodomain transcription factor Nkx2.2 at two distinct stages [14].

Regulatory relationships of Nkx2-2

  • Nkx2.2 was widely expressed in the ventricular zone of presumptive ZLI and also as a narrow band in the mantle zone [15].
  • Olig3 was co-expressed with Nkx2.2 in the lateral margin of the p3 domain [16].
  • At later times, a cooperative interaction is noted because Nkx2.2 promotes maturation of oligodendrocyte progenitor cells specified by expression of Olig2 [14].
  • The homeodomain-containing transcription factor Nkx2.9 is expressed in the ventralmost neural progenitor domain of the neural tube together with the related protein Nkx2.2 during early mouse embryogenesis [17].

Other interactions of Nkx2-2

  • Taken together, we propose that a combination of a loss-of-function mutation of Pax1 and a gain-of-function mutation of Nkx2-2 is the molecular basis of the Pax1(Un-s) mutation [10].
  • Nkx2-9 expression overlaps with that of Nkx2-2 but is generally broader [18].
  • In particular, the transcription factors (TFs) Olig2, Pax6, and Nkx2.2 have been shown to be important in the specification and/or maturation of the OG lineage [19].
  • First, duct cells proliferated in the perfused segment, then cells co-expressing multiple islet hormones and transcription factors such as PDX-1, Nkx2.2, Isl1, and Pax6 were observed in duct cells, and newly formed islet-like cell clusters (ICCs) containing beta cells were recognized [20].
  • Thus, Nkx2.2 has an essential role in interpreting graded Shh signals and selecting neuronal identity [2].

Analytical, diagnostic and therapeutic context of Nkx2-2


  1. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Sussel, L., Kalamaras, J., Hartigan-O'Connor, D.J., Meneses, J.J., Pedersen, R.A., Rubenstein, J.L., German, M.S. Development (1998) [Pubmed]
  2. Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Briscoe, J., Sussel, L., Serup, P., Hartigan-O'Connor, D., Jessell, T.M., Rubenstein, J.L., Ericson, J. Nature (1999) [Pubmed]
  3. Ascl1/Mash1 is required for the development of central serotonergic neurons. Pattyn, A., Simplicio, N., van Doorninck, J.H., Goridis, C., Guillemot, F., Brunet, J.F. Nat. Neurosci. (2004) [Pubmed]
  4. Regional expression of the homeobox gene Nkx-2.2 in the developing mammalian forebrain. Price, M., Lazzaro, D., Pohl, T., Mattei, M.G., Rüther, U., Olivo, J.C., Duboule, D., Di Lauro, R. Neuron (1992) [Pubmed]
  5. Transcription factor occupancy of the insulin gene in vivo. Evidence for direct regulation by Nkx2.2. Cissell, M.A., Zhao, L., Sussel, L., Henderson, E., Stein, R. J. Biol. Chem. (2003) [Pubmed]
  6. Integration of anteroposterior and dorsoventral regulation of Phox2b transcription in cranial motoneuron progenitors by homeodomain proteins. Samad, O.A., Geisen, M.J., Caronia, G., Varlet, I., Zappavigna, V., Ericson, J., Goridis, C., Rijli, F.M. Development (2004) [Pubmed]
  7. Interactions between areas I and II direct pdx-1 expression specifically to islet cell types of the mature and developing pancreas. Van Velkinburgh, J.C., Samaras, S.E., Gerrish, K., Artner, I., Stein, R. J. Biol. Chem. (2005) [Pubmed]
  8. The cDNA sequence of murine Nkx-2.2. Hartigan, D.J., Rubenstein, J.L. Gene (1996) [Pubmed]
  9. Lmx1b, Pet-1, and Nkx2.2 coordinately specify serotonergic neurotransmitter phenotype. Cheng, L., Chen, C.L., Luo, P., Tan, M., Qiu, M., Johnson, R., Ma, Q. J. Neurosci. (2003) [Pubmed]
  10. Undulated short-tail deletion mutation in the mouse ablates Pax1 and leads to ectopic activation of neighboring Nkx2-2 in domains that normally express Pax1. Kokubu, C., Wilm, B., Kokubu, T., Wahl, M., Rodrigo, I., Sakai, N., Santagati, F., Hayashizaki, Y., Suzuki, M., Yamamura, K., Abe, K., Imai, K. Genetics (2003) [Pubmed]
  11. Gliogenic radial glial cells show heterogeneity in the developing mouse spinal cord. Ogawa, Y., Takebayashi, H., Takahashi, M., Osumi, N., Iwasaki, Y., Ikenaka, K. Dev. Neurosci. (2005) [Pubmed]
  12. Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Prado, C.L., Pugh-Bernard, A.E., Elghazi, L., Sosa-Pineda, B., Sussel, L. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  13. Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain transcription factor. Qi, Y., Cai, J., Wu, Y., Wu, R., Lee, J., Fu, H., Rao, M., Sussel, L., Rubenstein, J., Qiu, M. Development (2001) [Pubmed]
  14. Cross-repressive interaction of the Olig2 and Nkx2.2 transcription factors in developing neural tube associated with formation of a specific physical complex. Sun, T., Dong, H., Wu, L., Kane, M., Rowitch, D.H., Stiles, C.D. J. Neurosci. (2003) [Pubmed]
  15. Expression patterns of Brx1 (Rieg gene), Sonic hedgehog, Nkx2.2, Dlx1 and Arx during zona limitans intrathalamica and embryonic ventral lateral geniculate nuclear formation. Kitamura, K., Miura, H., Yanazawa, M., Miyashita, T., Kato, K. Mech. Dev. (1997) [Pubmed]
  16. Non-overlapping expression of Olig3 and Olig2 in the embryonic neural tube. Takebayashi, H., Ohtsuki, T., Uchida, T., Kawamoto, S., Okubo, K., Ikenaka, K., Takeichi, M., Chisaka, O., Nabeshima, Y. Mech. Dev. (2002) [Pubmed]
  17. Targeted disruption of the homeobox gene Nkx2.9 reveals a role in development of the spinal accessory nerve. Pabst, O., Rummelies, J., Winter, B., Arnold, H.H. Development (2003) [Pubmed]
  18. Nkx2-9 is a novel homeobox transcription factor which demarcates ventral domains in the developing mouse CNS. Pabst, O., Herbrand, H., Arnold, H.H. Mech. Dev. (1998) [Pubmed]
  19. Early stages of oligodendrocyte development in the embryonic murine spinal cord proceed normally in the absence of Hoxa2. Nicolay, D.J., Doucette, J.R., Nazarali, A.J. Glia (2004) [Pubmed]
  20. Beta cell neogenesis from ducts and phenotypic conversion of residual islet cells in the adult pancreas of glucose intolerant mice induced by selective alloxan perfusion. Li, M., Miyagawa, J., Yamamoto, K., Moriwaki, M., Imagawa, A., Iwahashi, H., Yamagata, K., Tochino, Y., Hanafusa, T., Matsuzawa, Y. Endocr. J. (2002) [Pubmed]
  21. Expression profile of MODY3/HNF-1alpha protein in the developing mouse pancreas. Nammo, T., Yamagata, K., Hamaoka, R., Zhu, Q., Akiyama, T.E., Gonzalez, F.J., Miyagawa, J., Matsuzawa, Y. Diabetologia (2002) [Pubmed]
  22. A strong nerve dependence of sonic hedgehog expression in basal cells in mouse taste bud and an autonomous transcriptional control of genes in differentiated taste cells. Miura, H., Kato, H., Kusakabe, Y., Tagami, M., Miura-Ohnuma, J., Ninomiya, Y., Hino, A. Chem. Senses (2004) [Pubmed]
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