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Gene Review

Tlx2  -  T cell leukemia, homeobox 2

Mus musculus

Synonyms: Enteric neuron homeobox protein, Enx, Homeobox TLX-2, Homeobox protein Hox-11L1, Hox11L.1, ...
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Disease relevance of Tlx2

  • Tlx1-deficient and Enx-deficient mice display phenotypes in tissues where the mutated gene is singularly expressed, resulting in asplenogenesis and hyperganglionic megacolon, respectively [1].
  • Enx (Hox11L1)-deficient mice develop myenteric neuronal hyperplasia and megacolon [2].
  • The number of myenteric ganglia, total neurons per ganglion, and NADPH diaphorase presumptive inhibitory neurons per ganglion are increased in the proximal and distal colon, but decreased in the distal ileum of all Enx-/- mice [2].
  • Overexpression of calsequestrin (CSQ) induces severe cardiac hypertrophy, whereas overexpression of Na(+)-Ca(2+) exchanger (NCX) does not affect cardiac weight [3].
  • 2 Since hydrocortisone is the most widely used anti-inflammatory drug for the treatment of skin inflammation, we compared the anti-inflammatory effects of hydrocortisone to an NO-releasing derivative of hydrocortisone, NCX 1022, in a murine model of irritant contact dermatitis, induced by epidermal application of benzalkonium chloride [4].

High impact information on Tlx2

  • Enx-deficient mice develop megacolon with massive distension of the proximal colon [2].
  • The plasma membrane Na(+)/Ca(2+) exchanger (NCX) plays a role in regulation of intracellular Ca(2+) concentration via the forward mode (Ca(2+) efflux) or the reverse mode (Ca(2+) influx) [5].
  • The Ncx/Hox11L.1 gene, a member of the Hox11 homeobox gene family, is mainly expressed in neural crest-derived tissues [6].
  • We propose that Ncx/Hox11L.1 is required for maintenance of proper functions of the enteric nervous system [6].
  • To elucidate the role of Ncx/Hox11L.1, the gene has been inactivated in embryonic stem cells by homologous recombination [6].

Chemical compound and disease context of Tlx2


Biological context of Tlx2

  • Genetic mapping of two mouse homeobox genes Tlx-1 and Tlx-2 to murine chromosomes 19 and 6 [9].
  • The proposed gene orders and genetic distances for Tlx-1 and Tlx-2 are centromere 19-Lpc-1-(25.53 cM)-Pltr-4-(5.32 cM)-Tlx-1- (3.19 cM)-Ins-1-(7.45 cM)-Xmv-18, and centromere 6-Tcrb-(12.90 cM)-Mltr-3-(10.75 cM)-Tlx-2-(18.42 cM)-Xmv-6 [9].
  • Moreover, NCX 6550 potently inhibited cell proliferation in rat aortic smooth muscle cells (IC(50) = 2.2 +/- 0.3 microM) with a mechanism that involved both the polyamine and HMG-CoA reductase signaling pathways [10].
  • Animals with the normal canine NCX transgene showed Ca activation, whereas animals with the mutant transgene did not, confirming the role of this region in the process [11].
  • In native ferret cells and in mice with expressed canine NCX, allosteric regulation by Ca occurs under physiological conditions (K(mCaAct) = 125 +/- 16 nM SEM approximately resting [Ca](i)) [11].

Anatomical context of Tlx2

  • Tlx-2 is a homeobox gene expressed in the primitive streak of mouse embryos [12].
  • In PC12 cells, unlike their native statins, both compounds stimulated cGMP formation (NCX 6550, EC(50) = 2.3 +/- 0.2 microM; NCX 6553, EC(50) = 2.7 +/- 0.2 microM) [10].
  • Our results indicate that co-expression of Na(v)1.6 and NCX is associated with axonal injury in the spinal cord in EAE [13].
  • Ca activation of I(NCX) was observed in ferret myocytes but not in wild-type mouse myocytes, suggesting that Ca regulation of NCX may be species dependent [11].
  • Whether Ca(2+) influx on the Na/Ca exchanger (NCX) can trigger elementary sarcoplasmic reticulum (SR) Ca(2+) release events (Ca(2+) sparks) is controversial [14].

Associations of Tlx2 with chemical compounds

  • In RAW 264.7 murine macrophage cells stimulated with lipopolysaccharide (1 microg/ml), NCX 6550, but not pravastatin, significantly decreased inducible NO synthase and cyclooxygenase-2 protein expression as well as nitrite accumulation [10].
  • Hence, mevalonate or putrescine partially reverted the effects of NCX 6550 and their combination was fully effective [10].
  • With the aim of enhancing the nonlipid-lowering properties of selected statins, we introduced a NO-releasing moiety into the structure of pravastatin (NCX 6550) and fluvastatin (NCX 6553) [10].
  • According to our model, 50 to 64% of initial Ca(2+) removal is via the SERCA pump, whereas the NCX contributes 21-30% of the extrusion at high [Ca(2+)](i), and the PMCA contributes 21-27% at low [Ca(2+)](i) [15].
  • The remaining thapsigargin-insensitive decay was slowed further by inhibition of the plasma membrane Ca(2+)-ATPase (PMCA) and plasma membrane Na(+)/Ca(2+) exchanger (NCX) via alkalization of the bath solution, by adding lanthanum, or by substitution of Na(+) with Li(+) [15].

Other interactions of Tlx2


Analytical, diagnostic and therapeutic context of Tlx2

  • 2. Using triple-labelled fluorescent immunohistochemistry, we demonstrate that 73.5 +/- 4.3% of beta-APP positive axons co-express Na(v)1.6 and NCX, compared with 4.4 +/- 1.0% in beta-APP negative axons [13].
  • Expression of NCX in duodenal mucosae was analyzed by Western blot, and cytosolic Ca(2+) in duodenocytes was measured by fura 2 [16].
  • These results indicate that Ca(2+) entering the myocyte via NCX can cause Ca(2+) sparks which are similar to those elicited by electrical stimulation [14].
  • Inhibition of SERCA2 and NCX as well as gene targeting all prolonged the relaxation half-time [17].
  • The contractile function in NCX KO mice hearts was significantly better than that in wild type (WT) mice hearts after ischemia/reperfusion and the infarct size was significantly small in NCX KO mice hearts compared with that in WT mice hearts [18].


  1. Rnx deficiency results in congenital central hypoventilation. Shirasawa, S., Arata, A., Onimaru, H., Roth, K.A., Brown, G.A., Horning, S., Arata, S., Okumura, K., Sasazuki, T., Korsmeyer, S.J. Nat. Genet. (2000) [Pubmed]
  2. Enx (Hox11L1)-deficient mice develop myenteric neuronal hyperplasia and megacolon. Shirasawa, S., Yunker, A.M., Roth, K.A., Brown, G.A., Horning, S., Korsmeyer, S.J. Nat. Med. (1997) [Pubmed]
  3. Functional properties of transgenic mouse hearts overexpressing both calsequestrin and the Na(+)-Ca(2+) exchanger. Linck, B., Bokník, P., Huke, S., Kirchhefer, U., Knapp, J., Lüss, H., Müller, F.U., Neumann, J., Tanriseven, Z., Vahlensieck, U., Baba, H.A., Jones, L.R., Philipson, K.D., Schmitz, W. J. Pharmacol. Exp. Ther. (2000) [Pubmed]
  4. Anti-inflammatory effects of nitric oxide-releasing hydrocortisone NCX 1022, in a murine model of contact dermatitis. Hyun, E., Bolla, M., Steinhoff, M., Wallace, J.L., Soldato, P.D., Vergnolle, N. Br. J. Pharmacol. (2004) [Pubmed]
  5. Enhanced learning and memory in mice lacking Na+/Ca2+ exchanger 2. Jeon, D., Yang, Y.M., Jeong, M.J., Philipson, K.D., Rhim, H., Shin, H.S. Neuron (2003) [Pubmed]
  6. A novel pathogenesis of megacolon in Ncx/Hox11L.1 deficient mice. Hatano, M., Aoki, T., Dezawa, M., Yusa, S., Iitsuka, Y., Koseki, H., Taniguchi, M., Tokuhisa, T. J. Clin. Invest. (1997) [Pubmed]
  7. Prevention of pulmonary thromboembolism by NCX 4016, a nitric oxide-releasing aspirin. Momi, S., Emerson, M., Paul, W., Leone, M., Mezzasoma, A.M., Del Soldato, P., Page, C.P., Gresele, P. Eur. J. Pharmacol. (2000) [Pubmed]
  8. Nitric oxide-releasing aspirin derivative, NCX 4016, promotes reparative angiogenesis and prevents apoptosis and oxidative stress in a mouse model of peripheral ischemia. Emanueli, C., Van Linthout, S., Salis, M.B., Monopoli, A., Del Soldato, P., Ongini, E., Madeddu, P. Arterioscler. Thromb. Vasc. Biol. (2004) [Pubmed]
  9. Genetic mapping of two mouse homeobox genes Tlx-1 and Tlx-2 to murine chromosomes 19 and 6. Wen, X.Y., Tang, S., Breitman, M.L. Genomics (1994) [Pubmed]
  10. Nitric oxide (NO)-releasing statin derivatives, a class of drugs showing enhanced antiproliferative and antiinflammatory properties. Ongini, E., Impagnatiello, F., Bonazzi, A., Guzzetta, M., Govoni, M., Monopoli, A., Del Soldato, P., Ignarro, L.J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  11. Allosteric regulation of Na/Ca exchange current by cytosolic Ca in intact cardiac myocytes. Weber, C.R., Ginsburg, K.S., Philipson, K.D., Shannon, T.R., Bers, D.M. J. Gen. Physiol. (2001) [Pubmed]
  12. The Tlx-2 homeobox gene is a downstream target of BMP signalling and is required for mouse mesoderm development. Tang, S.J., Hoodless, P.A., Lu, Z., Breitman, M.L., McInnes, R.R., Wrana, J.L., Buchwald, M. Development (1998) [Pubmed]
  13. Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE. Craner, M.J., Hains, B.C., Lo, A.C., Black, J.A., Waxman, S.G. Brain (2004) [Pubmed]
  14. Ca2+ sparks induced by Na/Ca exchange. Ritter, M., Sui, Z., Philipson, K.D., Li, F., Spitzer, K.W., Ishida, H., Barry, W.H. Cell Calcium (2003) [Pubmed]
  15. Dynamics of calcium clearance in mouse pancreatic beta-cells. Chen, L., Koh, D.S., Hille, B. Diabetes (2003) [Pubmed]
  16. Na(+)/Ca(2+) exchange regulates Ca(2+)-dependent duodenal mucosal ion transport and HCO(3)(-) secretion in mice. Dong, H., Sellers, Z.M., Smith, A., Chow, J.Y., Barrett, K.E. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  17. Role of plasma membrane Ca2+-ATPase in contraction-relaxation processes of the bladder: evidence from PMCA gene-ablated mice. Liu, L., Ishida, Y., Okunade, G., Shull, G.E., Paul, R.J. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  18. Role of Na+-Ca2+ exchanger in myocardial ischemia/reperfusion injury: evaluation using a heterozygous Na+-Ca2+ exchanger knockout mouse model. Ohtsuka, M., Takano, H., Suzuki, M., Zou, Y., Akazawa, H., Tamagawa, M., Wakimoto, K., Nakaya, H., Komuro, I. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
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