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Gene Review

Pax2  -  paired box 2

Mus musculus

Synonyms: Opdc, Paired box protein Pax-2, Pax-2
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Disease relevance of Pax2

  • To identify potential genes regulated by the Pax2 protein, we screened embryonic kidney cells transformed with Pax2-expressing retroviruses for genes activated in response to Pax2 expression [1].
  • Furthermore, Pax2 mutants show extension of the pigmented retina into the optic stalks and failure of the optic fissure to close resulting in coloboma [2].
  • Persistent expression of Pax2 did not interfere with the initial differentiation of podocytes, but mice ectopically expressing PAX2 developed end-stage renal failure soon after birth [3].
  • This results in an abnormal organization of the Pax2+ cells and ganglion cell axons at the nascent optic disc [4].
  • To assess the role of Pax2 during the development of polycystic kidney disease, the progression of renal cysts was examined in cpk mutants carrying one or two alleles of Pax2 [5].

High impact information on Pax2

  • LIF acted on epithelial precursors that we identified by the expression of Pax2 and Wnt4 [6].
  • In the developing kidney, Pax-2 is expressed in the induced mesenchyme, in the ureter epithelium, and in early epithelial structures derived from the mesenchyme [7].
  • The data obtained with four independently derived transgenic embryos and with one transgenic line demonstrate that deregulated Pax-2 expression results in histologically abnormal and dysfunctional renal epithelium with properties similar to congenital nephrotic syndrome [7].
  • Thus, repression of Pax-2 is required for normal kidney development and persistent expression of Pax-2 may restrict the differentiation potential of renal epithelial cells [7].
  • Nephric lineage specification by Pax2 and Pax8 [8].

Biological context of Pax2

  • The transgene-induced Krd mutation corresponds to an approximately 7-centimorgan chromosome 19 deletion that eliminates the entire Pax2 locus [9].
  • We describe a new mouse frameshift mutation (Pax2(1Neu)) with a 1-bp insertion in the Pax2 gene [10].
  • Moreover, transcription factors En1 and Pax2 were also downregulated prior to the 4-somite stage, whereas Gbx2 downregulation occurred at the 4-somite stage [11].
  • Although the amount of Pax2-dependent transactivation was low in transient assays, the data suggests that local alterations of chromatin structure by Pax proteins can greatly enhance expression when presented in the right cellular context [1].
  • In the mouse, homozygous Pax2 inactivation results in renal agenesis, a phenotype that has largely precluded the analysis of Pax gene function during metanephric kidney development [12].

Anatomical context of Pax2

  • Conversely, retroviral misexpression of Pax2 was sufficient to induce ectopic nephric structures in the intermediate mesoderm and genital ridge of chick embryos [8].
  • Cooperation of Pax2 and Pax5 in midbrain and cerebellum development [9].
  • Expression of the two closely related transcription factors Pax2 and Pax5 overlaps spatially and temporally in this region of the developing central nervous system [9].
  • Retinal pigmented epithelium determination requires the redundant activities of Pax2 and Pax6 [13].
  • These include early-born dI4 and dI6 inhibitory interneurons, as well as late-born inhibitory dIL(A) neurons (dIL(A)), all of which express the paired-domain transcription factor Pax2 [14].

Associations of Pax2 with chemical compounds

  • At the morphological level, Pax2(+/-)Pax8(+/-) metanephric kidneys are severely hypodysplastic and characterized by a reduction in ureter tips and nephron number in comparison with wild-type or Pax2(+/-) kidneys [12].
  • Treating Brattleboro rats with desamino-Cys-1,d-Arg-8 vasopressin, which increases inner-medullary NaCl concentration, causes a 4-fold increase in inner-medullary Pax2 protein [15].
  • During kidney development, Pax2 and Pax8 are expressed very early in the mammalian nephric duct and both precede the expression of receptor tyrosine kinase, c-Ret [16].
  • The truncated Pax8 protein becomes more similar to the predicted murine Pax2 protein, that is also expressed during kidney development and lacks the serine rich region [17].
  • Similarly, Pax2 overexpression in RCC cells contributes to cisplatin resistance [18].

Physical interactions of Pax2

  • Together these data indicate that Pax2 and homeodomain proteins directly bind to and cooperatively regulate the mhb enhancer of Pax5 [19].
  • The two Pax2/5/8-binding sites were deleted from the En2 locus and replaced with the bacterial neo gene by homologous recombination in mouse embryonic stem cells [20].

Regulatory relationships of Pax2

  • Pax2 is expressed in epithelial cells of the ventral part of the membranous labyrinth where it overlaps with the Nkx5 expression domain. sek shows a complementary pattern to Nkx5 in the vestibular epithelium [21].
  • To investigate whether these contrasting phenotypes are caused by differences in the temporal expression or biochemical activity of these two transcription factors, we have generated a knock-in (ki) mouse, which expresses a Pax5 minigene under the control of the Pax2 locus [22].
  • Ectopic expression of Pax6 in the optic stalk under control of Pax2 promoter elements resulted in a shift of the optic cup/optic stalk boundary indicated by the presence of retinal pigmented cells on the optic stalk [23].
  • Molecular analysis indicated that Pax2 was expressed normally but the expression of Wnt9b and E-cadherin in the nephric duct was markedly altered [24].
  • The Kidney and retinal defects (Krd) mouse carries a 7-cM transgene-induced deletion on chromosome 19 that includes the Pax2 locus [4].

Other interactions of Pax2

  • In these triple mutants, the metanephric blastema condenses, and expression of early patterning genes, Pax2 and Wt1, is unperturbed [25].
  • In these mutants, the isthmic organizer cells prematurely differentiate into neurons and terminate expression of secreting molecules such as Fgf8 and Wnt1 and the paired box genes Pax2/5, all of which are essential for the isthmic organizer function [26].
  • Lack of pigment epithelium specification was associated with an expansion of the prospective neural retina and optic stalk territories, as determined by the expression of Pax6, Six3 and Pax2 [27].
  • The paired domain transcription factor Pax2 is required for the formation of the isthmic organizer (IsO) at the midbrain-hindbrain boundary, where it initiates expression of the IsO signal Fgf8 [28].
  • The expression pattern of Pax2 appeared normal; Cryaa expression could not be detected [29].

Analytical, diagnostic and therapeutic context of Pax2

  • In the present study, we find by cDNA microarray analysis that Pax2 expression in second-passage mouse inner-medullary epithelial cells is increased by a high NaCl concentration, which is significant because NaCl levels are normally high in the inner medulla in vivo, and varies with urinary concentration [15].
  • Pax2 expression occurs in renal medullary epithelial cells in vivo and in cell culture, is osmoregulated, and promotes osmotic tolerance [15].
  • The expression of the murine paired-box-containing gene, Pax2, is examined in the developing central nervous system by in situ hybridization [30].
  • However, GDNF replacement in organ culture is not sufficient to stimulate ureteric bud outgrowth from Pax2 mutant nephric ducts, indicating additional defects in the nephric duct epithelium of Pax2 mutants [31].
  • To understand the embryonic basis of ocular defects observed in adult Krd/+ mice, we used immunohistochemistry, digital three-dimensional reconstructions, and quantitative morphometry to examine Pax2 protein distribution and ocular development in normal and Krd/+ mice from E10.5 to P2 [4].


  1. The secreted frizzled related protein 2 (SFRP2) gene is a target of the Pax2 transcription factor. Brophy, P.D., Lang, K.M., Dressler, G.R. J. Biol. Chem. (2003) [Pubmed]
  2. Pax2 contributes to inner ear patterning and optic nerve trajectory. Torres, M., Gómez-Pardo, E., Gruss, P. Development (1996) [Pubmed]
  3. An inducible mouse model for PAX2-dependent glomerular disease: insights into a complex pathogenesis. Wagner, K.D., Wagner, N., Guo, J.K., Elger, M., Dallman, M.J., Bugeon, L., Schedl, A. Curr. Biol. (2006) [Pubmed]
  4. Pax2 expression and retinal morphogenesis in the normal and Krd mouse. Otteson, D.C., Shelden, E., Jones, J.M., Kameoka, J., Hitchcock, P.F. Dev. Biol. (1998) [Pubmed]
  5. Reduced Pax2 gene dosage increases apoptosis and slows the progression of renal cystic disease. Ostrom, L., Tang, M.J., Gruss, P., Dressler, G.R. Dev. Biol. (2000) [Pubmed]
  6. Mesenchymal to epithelial conversion in rat metanephros is induced by LIF. Barasch, J., Yang, J., Ware, C.B., Taga, T., Yoshida, K., Erdjument-Bromage, H., Tempst, P., Parravicini, E., Malach, S., Aranoff, T., Oliver, J.A. Cell (1999) [Pubmed]
  7. Deregulation of Pax-2 expression in transgenic mice generates severe kidney abnormalities. Dressler, G.R., Wilkinson, J.E., Rothenpieler, U.W., Patterson, L.T., Williams-Simons, L., Westphal, H. Nature (1993) [Pubmed]
  8. Nephric lineage specification by Pax2 and Pax8. Bouchard, M., Souabni, A., Mandler, M., Neubüser, A., Busslinger, M. Genes Dev. (2002) [Pubmed]
  9. Cooperation of Pax2 and Pax5 in midbrain and cerebellum development. Urbánek, P., Fetka, I., Meisler, M.H., Busslinger, M. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  10. The mouse Pax2(1Neu) mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney. Favor, J., Sandulache, R., Neuhäuser-Klaus, A., Pretsch, W., Chatterjee, B., Senft, E., Wurst, W., Blanquet, V., Grimes, P., Spörle, R., Schughart, K. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  11. Lmx1b is essential for Fgf8 and Wnt1 expression in the isthmic organizer during tectum and cerebellum development in mice. Guo, C., Qiu, H.Y., Huang, Y., Chen, H., Yang, R.Q., Chen, S.D., Johnson, R.L., Chen, Z.F., Ding, Y.Q. Development (2007) [Pubmed]
  12. Pax2 and pax8 regulate branching morphogenesis and nephron differentiation in the developing kidney. Narlis, M., Grote, D., Gaitan, Y., Boualia, S.K., Bouchard, M. J. Am. Soc. Nephrol. (2007) [Pubmed]
  13. Retinal pigmented epithelium determination requires the redundant activities of Pax2 and Pax6. Bäumer, N., Marquardt, T., Stoykova, A., Spieler, D., Treichel, D., Ashery-Padan, R., Gruss, P. Development (2003) [Pubmed]
  14. Lhx1 and Lhx5 maintain the inhibitory-neurotransmitter status of interneurons in the dorsal spinal cord. Pillai, A., Mansouri, A., Behringer, R., Westphal, H., Goulding, M. Development (2007) [Pubmed]
  15. Pax2 expression occurs in renal medullary epithelial cells in vivo and in cell culture, is osmoregulated, and promotes osmotic tolerance. Cai, Q., Dmitrieva, N.I., Ferraris, J.D., Brooks, H.L., van Balkom, B.W., Burg, M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  16. Regulation of c-Ret in the developing kidney is responsive to Pax2 gene dosage. Clarke, J.C., Patel, S.R., Raymond, R.M., Andrew, S., Robinson, B.G., Dressler, G.R., Brophy, P.D. Hum. Mol. Genet. (2006) [Pubmed]
  17. PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms' tumors. Poleev, A., Fickenscher, H., Mundlos, S., Winterpacht, A., Zabel, B., Fidler, A., Gruss, P., Plachov, D. Development (1992) [Pubmed]
  18. PAX2 inactivation enhances cisplatin-induced apoptosis in renal carcinoma cells. Hueber, P.A., Waters, P., Clarke, P., Eccles, M., Goodyer, P. Kidney Int. (2006) [Pubmed]
  19. Pax2 and homeodomain proteins cooperatively regulate a 435 bp enhancer of the mouse Pax5 gene at the midbrain-hindbrain boundary. Pfeffer, P.L., Bouchard, M., Busslinger, M. Development (2000) [Pubmed]
  20. Two Pax2/5/8-binding sites in Engrailed2 are required for proper initiation of endogenous mid-hindbrain expression. Li Song, D., Joyner, A.L. Mech. Dev. (2000) [Pubmed]
  21. Regionalized expression of Nkx5-1, Nkx5-2, Pax2 and sek genes during mouse inner ear development. Rinkwitz-Brandt, S., Arnold, H.H., Bober, E. Hear. Res. (1996) [Pubmed]
  22. Functional equivalence of the transcription factors Pax2 and Pax5 in mouse development. Bouchard, M., Pfeffer, P., Busslinger, M. Development (2000) [Pubmed]
  23. Spatial specification of mammalian eye territories by reciprocal transcriptional repression of Pax2 and Pax6. Schwarz, M., Cecconi, F., Bernier, G., Andrejewski, N., Kammandel, B., Wagner, M., Gruss, P. Development (2000) [Pubmed]
  24. Lim 1 is required for nephric duct extension and ureteric bud morphogenesis. Pedersen, A., Skjong, C., Shawlot, W. Dev. Biol. (2005) [Pubmed]
  25. Hox11 paralogous genes are essential for metanephric kidney induction. Wellik, D.M., Hawkes, P.J., Capecchi, M.R. Genes Dev. (2002) [Pubmed]
  26. Hes1 and Hes3 regulate maintenance of the isthmic organizer and development of the mid/hindbrain. Hirata, H., Tomita, K., Bessho, Y., Kageyama, R. EMBO J. (2001) [Pubmed]
  27. Otx genes are required for tissue specification in the developing eye. Martinez-Morales, J.R., Signore, M., Acampora, D., Simeone, A., Bovolenta, P. Development (2001) [Pubmed]
  28. Identification of Pax2-regulated genes by expression profiling of the mid-hindbrain organizer region. Bouchard, M., Grote, D., Craven, S.E., Sun, Q., Steinlein, P., Busslinger, M. Development (2005) [Pubmed]
  29. Aphakia (ak), a mouse mutation affecting early eye development: fine mapping, consideration of candidate genes and altered Pax6 and Six3 gene expression pattern. Grimm, C., Chatterjee, B., Favor, J., Immervoll, T., Löster, J., Klopp, N., Sandulache, R., Graw, J. Dev. Genet. (1998) [Pubmed]
  30. Spatially and temporally restricted expression of Pax2 during murine neurogenesis. Nornes, H.O., Dressler, G.R., Knapik, E.W., Deutsch, U., Gruss, P. Development (1990) [Pubmed]
  31. Regulation of ureteric bud outgrowth by Pax2-dependent activation of the glial derived neurotrophic factor gene. Brophy, P.D., Ostrom, L., Lang, K.M., Dressler, G.R. Development (2001) [Pubmed]
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