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Gene Review

Pax8  -  paired box 8

Mus musculus

Synonyms: Paired box protein Pax-8, Pax-8
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Disease relevance of Pax8

  • Expression of pituitary hormones in the Pax8-/- mouse model of congenital hypothyroidism [1].
  • These animals closely resemble the phenotype of Pax8(-/-) mice, including growth retardation and a completely distorted appearance of the pituitary with thyrotroph hyperplasia and hypertrophy, extremely high TSH mRNA levels, reduced GH mRNA expression, and the almost complete absence of lactotrophs [2].
  • The hearing loss and also the recovery effect by T(4) substitution in Pax8-/- mice is larger than that in the other models [3].
  • Thus, infertility in Pax8(-/-) mice seems to be due to a defect in development of the Müllerian duct rather than to hormonal imbalance, pointing to a direct morphogenic role for Pax8 in uterine development [4].
  • Transfection of N2A neuroblastoma cells with the Pax-8 expression vector resulted in a 5-fold increase in the transcription of the endogenous n-cam gene [5].

High impact information on Pax8

  • Follicular cells of the thyroid gland require Pax8 gene function [6].
  • We present evidence that Pax8 is necessary for providing cues for the differentiation of competent endoderm primordia into thyroxin-producing follicular cells [6].
  • Nephric lineage specification by Pax2 and Pax8 [7].
  • Alternatively spliced insertions in the paired domain restrict the DNA sequence specificity of Pax6 and Pax8 [8].
  • We now demonstrate that the mammalian Pax8 gene gives rise, by alternative mRNA splicing, to a protein isoform containing an extra serine residue in the recognition alpha-helix 3 of the paired domain [8].

Chemical compound and disease context of Pax8


Biological context of Pax8

  • Using an interspecies backcross system, we have mapped the Pax8 gene within the proximal portion of mouse chromosome 2 in a close linkage to the surf locus [10].
  • In situ hybridization was used to determine the pattern of Pax8 expression during mouse embryogenesis [10].
  • Pax8 is expressed transiently between 11.5 and 12.5 days of gestation along the rostrocaudal axis extending from the myelencephalon throughout the length of the neural tube, predominantly in two parallel regions on either side of the basal plate [10].
  • Here we describe the isolation of Pax8, a novel paired box containing clone from an 8.5 day p.c. mouse embryo cDNA library [10].
  • Together, these results demonstrate a crucial role for Pax2 and Pax8 in nephron differentiation and branching morphogenesis of the metanephros [11].

Anatomical context of Pax8

  • These data are consistent with a role for Pax8 in the induction of kidney epithelium [10].
  • In the mesonephros and metanephros the expression of Pax8 was localized to the mesenchymal condensations, which are induced by the nephric duct and ureter, respectively [10].
  • A precise comparison between the two types of mutants reveals that their phenotypes are similar, but the defects in spleen, bone, and small intestine are more pronounced in Pax8(-/-) mice [12].
  • Alkaline phosphatase expression was additionally detected in the adrenal gland and in the facial, vestibulocochlear, and cuneate nerves, which have so far not been associated with Pax8 expression [13].
  • Abnormalities in the outer and middle ear structures were found in a considerable percentage of Pax8-/- animals [3].

Associations of Pax8 with chemical compounds

  • 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 [14].
  • This is interpreted as the result of a negative effect of the unliganded TR on thyroid hormone target genes expression in the Pax8(-/-) mutants [12].
  • Neonatal Pax8(-/-) mice demonstrate an approximately 10-fold increase in hepatic triglyceride content associated with a decrease in hepatic apoB RNA editing [15].
  • Pax 8 expression in primary cultured dog thyrocyte is increased by cyclic AMP [16].

Regulatory relationships of Pax8

  • The expression of Foxe1 is regulated in an intriguing fashion as it is strongly dependent on the presence of Pax8 in thyroid precursor cells, while the expression of the same gene in the pharyngeal endoderm surrounding the primordium is dependent on Sonic hedgehog (Shh)-derived signaling [17].
  • These results suggest a possible endocrine role for Tg in regulating both Pax-8 related gene transcription and cell division in the mesangial cell [18].

Other interactions of Pax8

  • The expression of Pax5 and Pax8 is either not initiated at the midbrain-hindbrain boundary or is later not maintained in other expression domains [19].
  • A comparison with Notch1 and Pax5 and Pax8 expression in the embryonic mouse kidney helps support homology of the amphioxus and vertebrate kidneys [20].
  • Our data make it unlikely that us is a mutation in either Spna-2 or Pax-8 [21].
  • We have examined the thyroid hormone-dependent regulation of apolipoprotein B (apoB) RNA editing in a strain of congenitally hypothyroid mice (Pax8(-/-)) that lacks thyroid follicular cells [15].
  • As reported recently, Pax8(-/-) mice can also be rescued and survive to adulthood by the additional elimination of the entire thyroid hormone receptor alpha (TRalpha) gene, yielding Pax8(-/-)TRalpha(o/o) double-knockout animals [2].

Analytical, diagnostic and therapeutic context of Pax8


  1. Expression of pituitary hormones in the Pax8-/- mouse model of congenital hypothyroidism. Friedrichsen, S., Christ, S., Heuer, H., Schäfer, M.K., Parlow, A.F., Visser, T.J., Bauer, K. Endocrinology (2004) [Pubmed]
  2. Athyroid Pax8-/- mice cannot be rescued by the inactivation of thyroid hormone receptor alpha1. Mittag, J., Friedrichsen, S., Heuer, H., Polsfuss, S., Visser, T.J., Bauer, K. Endocrinology (2005) [Pubmed]
  3. Hearing loss in athyroid pax8 knockout mice and effects of thyroxine substitution. Christ, S., Biebel, U.W., Hoidis, S., Friedrichsen, S., Bauer, K., Smolders, J.W. Audiol. Neurootol. (2004) [Pubmed]
  4. Congenital hypothyroid female pax8-deficient mice are infertile despite thyroid hormone replacement therapy. Mittag, J., Winterhager, E., Bauer, K., Grümmer, R. Endocrinology (2007) [Pubmed]
  5. Binding and activation of the promoter for the neural cell adhesion molecule by Pax-8. Holst, B.D., Goomer, R.S., Wood, I.C., Edelman, G.M., Jones, F.S. J. Biol. Chem. (1994) [Pubmed]
  6. Follicular cells of the thyroid gland require Pax8 gene function. Mansouri, A., Chowdhury, K., Gruss, P. Nat. Genet. (1998) [Pubmed]
  7. Nephric lineage specification by Pax2 and Pax8. Bouchard, M., Souabni, A., Mandler, M., Neubüser, A., Busslinger, M. Genes Dev. (2002) [Pubmed]
  8. Alternatively spliced insertions in the paired domain restrict the DNA sequence specificity of Pax6 and Pax8. Kozmik, Z., Czerny, T., Busslinger, M. EMBO J. (1997) [Pubmed]
  9. Male congenital hypothyroid Pax8-/- mice are infertile despite adequate treatment with thyroid hormone. Wistuba, J., Mittag, J., Luetjens, C.M., Cooper, T.G., Yeung, C.H., Nieschlag, E., Bauer, K. J. Endocrinol. (2007) [Pubmed]
  10. Pax8, a murine paired box gene expressed in the developing excretory system and thyroid gland. Plachov, D., Chowdhury, K., Walther, C., Simon, D., Guenet, J.L., Gruss, P. Development (1990) [Pubmed]
  11. 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]
  12. Congenital hypothyroid Pax8(-/-) mutant mice can be rescued by inactivating the TRalpha gene. Flamant, F., Poguet, A.L., Plateroti, M., Chassande, O., Gauthier, K., Streichenberger, N., Mansouri, A., Samarut, J. Mol. Endocrinol. (2002) [Pubmed]
  13. Tissue-specific expression of cre recombinase from the Pax8 locus. Bouchard, M., Souabni, A., Busslinger, M. Genesis (2004) [Pubmed]
  14. 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]
  15. Thyroid hormone regulates hepatic triglyceride mobilization and apolipoprotein B messenger ribonucleic Acid editing in a murine model of congenital hypothyroidism. Mukhopadhyay, D., Plateroti, M., Anant, S., Nassir, F., Samarut, J., Davidson, N.O. Endocrinology (2003) [Pubmed]
  16. Pax 8 expression in primary cultured dog thyrocyte is increased by cyclic AMP. Van Renterghem, P., Vassart, G., Christophe, D. Biochim. Biophys. Acta (1996) [Pubmed]
  17. An integrated regulatory network controlling survival and migration in thyroid organogenesis. Parlato, R., Rosica, A., Rodriguez-Mallon, A., Affuso, A., Postiglione, M.P., Arra, C., Mansouri, A., Kimura, S., Di Lauro, R., De Felice, M. Dev. Biol. (2004) [Pubmed]
  18. Thyroglobulin increases cell proliferation and suppresses Pax-8 in mesangial cells. Sellitti, D.F., Suzuki, K., Doi, S.Q., LaGranha, C., Machado, M., Matos, T., Kohn, L.D. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  19. Characterization of three novel members of the zebrafish Pax2/5/8 family: dependency of Pax5 and Pax8 expression on the Pax2.1 (noi) function. Pfeffer, P.L., Gerster, T., Lun, K., Brand, M., Busslinger, M. Development (1998) [Pubmed]
  20. Characterization and developmental expression of the amphioxus homolog of Notch (AmphiNotch): evolutionary conservation of multiple expression domains in amphioxus and vertebrates. Holland, L.Z., Rached, L.A., Tamme, R., Holland, N.D., Kortschak, D., Inoko, H., Shiina, T., Burgtorf, C., Lardelli, M. Dev. Biol. (2001) [Pubmed]
  21. Urogenital syndrome (us): a developmental mutation on chromosome 2 of the mouse. Lane, P.W., Birkenmeier, C.S. Mamm. Genome (1993) [Pubmed]
  22. Thyroid hormone deficiency affects postnatal spiking activity and expression of Ca2+ and K+ channels in rodent inner hair cells. Brandt, N., Kuhn, S., Münkner, S., Braig, C., Winter, H., Blin, N., Vonthein, R., Knipper, M., Engel, J. J. Neurosci. (2007) [Pubmed]
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