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Gene Review

pax2a  -  paired box 2a

Danio rerio

Synonyms: No isthmus protein, PAXZF-B, Paired box protein Pax-2a, Pax-2, SO:0000704, ...
 
 
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Disease relevance of pax2a

 

High impact information on pax2a

  • Interestingly, ectopic expression of shh in the midbrain and elevated pax2a expression in the optic stalk were observed in foxl1 MO-injected embryos [2].
  • In contrast, the phenotype caused by disrupting foxi1, which is required for pax8 expression, was not enhanced by simultaneously disrupting pax8 [3].
  • Vertebrate Pax2 and Pax8 proteins are closely related transcription factors hypothesized to regulate early aspects of inner ear development [3].
  • To facilitate analysis of zebrafish pax8, we completed sequencing of the entire gene, including the 5' and 3' UTRs. pax8 transcripts undergo complex alternative splicing to generate at least ten distinct isoforms [3].
  • Maintenance of lmx1b.1 and lmx1b.2 expression at the isthmus requires the function of no isthmus/pax2.1, as well as Fgf signaling [4].
 

Biological context of pax2a

  • In accordance with these results, enhancer activity in the PB1-A region, as well as gbx2 expression in r1, was missing in no isthmus mutant embryos that lacked functional pax2a [5].
  • These effects were made manifest at early stages of otic development by an absence of early placode markers (pax2.1 and dlx3) but were not accompanied by effects on cell division or death [6].
  • Stable transgenic expression of this reporter gene shows that a 5.3-kb fragment of the 5' region contains most, but not all, elements required for driving pax2.1 expression [7].
  • Transgene activation in the pronephros and developing ear suggests that these pax2.1-expressing tissues are composed of independently regulated subdomains [7].
  • We demonstrate a requirement for pax2.1 in multiple aspects of pronephric development including tubule and duct epithelial differentiation and cloaca morphogenesis [8].
 

Anatomical context of pax2a

  • Thus, like pax2.1, both hhex and nk2.1a have similarly late roles in differentiation or growth of thyroid follicular cells, and here, we show that all three genes act in parallel rather than in a single pathway [9].
  • We propose that noi and ace are required for development of the MHB region and of the adjacent mid- and hindbrain, which are thought to be patterned by the MHB region [10].
  • We suggest that this novel feedback loop may allow continuation of pax2.1 expression, and hence development of the MHB organizer, to become independent of the patterning machinery of the gastrula embryo [7].
  • Pax6 protein is present in all cells that form the neural retina and pigment epithelium, whereas Pax2 is located primarily in cells that will give rise to the optic stalk [11].
  • Mutations in two genes affect the formation of the boundary between midbrain and hindbrain (MHB): no isthmus (noi) and acerebellar (ace). noi mutant embryos lack the MHB constriction, the cerebellum and optic tectum, as well as the pronephric duct [10].
 

Associations of pax2a with chemical compounds

  • Interestingly, the anterior non-follicular site of thyroid hormone production is not affected in noi(-/-) [1].
  • The results suggest that the failure in pronephric tubule differentiation in noi arises from a patterning defect during differentiation of the pronephric primordium and that mutually inhibitory regulatory interactions play an important role in defining the boundary between glomerular and tubule progenitors in the forming nephron [8].
  • We find that expression of two members of the Netrin family of axon guidance molecules and the signalling protein Sonic hedgehog is disturbed in noi- embryos, whereas several members of the Eph family of receptors and ligands show no obvious alterations in expression at the diencephalic midline [12].
 

Regulatory relationships of pax2a

  • These results suggest that a signal emanating from the midline, which is absent in cyclops mutant embryos, may be required to promote Pax2 and inhibit Pax6 expression in cells destined to form the optic stalks [11].
  • In aus mutant embryos, ace is upregulated at many sites in the embryo, while noi expression is only upregulated in regions of the forebrain and midbrain which also express ace [13].
  • The deltaA gene of zebrafish mediates lateral inhibition of hair cells in the inner ear and is regulated by pax2.1 [14].
 

Other interactions of pax2a

  • How the positional information is translated into activation of Pax2, Wnt1 and Fgf8 expression during MHB establishment remains unclear [15].
  • Thus, pax5 works in conjunction with fgf3 and pax2a to establish and/or maintain the utricular macula and is essential for vestibular function [16].
  • Otic expression of pax5 requires pax2a and fgf3, mutations in which cause vestibular defects, albeit by distinct mechanisms [16].
  • The sox3 domain, which is referred to here as the early lateral placode, is segregated during the early phase of segmentation to form a pax2a-positive medial area and a pax2a-negative lateral area [17].
  • Finally, we trace the molecular identity of GFP-positive cells in the acerebellar (ace) and no-isthmus (noi) mutant backgrounds to analyze directly fgf8 and pax2.1 mutant gene activities for their ultimate effect on cell fate [18].
 

Analytical, diagnostic and therapeutic context of pax2a

  • Using in situ hybridization of early brain marker genes, we found that the most striking effects were an increase in pax2.1 expression in eye stalks associated with absence of either form of PACAP or an increase in eng2 and fgf8 in the midbrain-hindbrain boundary after loss of PACAP2 [19].
  • Transplantations, mRNA injections and morpholino knock-down experiments show that this feedback regulation of pax2.1 transcription occurs cell-autonomously, and that it requires eng2 and eng3 as known targets for Pax2.1 regulation [7].

References

  1. Pax2.1 is required for the development of thyroid follicles in zebrafish. Wendl, T., Lun, K., Mione, M., Favor, J., Brand, M., Wilson, S.W., Rohr, K.B. Development (2002) [Pubmed]
  2. Transcriptional Repressor foxl1 Regulates Central Nervous System Development by Suppressing shh Expression in Zebra Fish. Nakada, C., Satoh, S., Tabata, Y., Arai, K., Watanabe, S. Mol. Cell. Biol. (2006) [Pubmed]
  3. Zebrafish pax8 is required for otic placode induction and plays a redundant role with Pax2 genes in the maintenance of the otic placode. Mackereth, M.D., Kwak, S.J., Fritz, A., Riley, B.B. Development (2005) [Pubmed]
  4. Zebrafish Lmx1b.1 and Lmx1b.2 are required for maintenance of the isthmic organizer. O'Hara, F.P., Beck, E., Barr, L.K., Wong, L.L., Kessler, D.S., Riddle, R.D. Development (2005) [Pubmed]
  5. Three enhancer regions regulate gbx2 gene expression in the isthmic region during zebrafish development. Islam, M.E., Kikuta, H., Inoue, F., Kanai, M., Kawakami, A., Parvin, M.S., Takeda, H., Yamasu, K. Mech. Dev. (2006) [Pubmed]
  6. Fgf3 and Fgf8 are required together for formation of the otic placode and vesicle. Maroon, H., Walshe, J., Mahmood, R., Kiefer, P., Dickson, C., Mason, I. Development (2002) [Pubmed]
  7. A novel positive transcriptional feedback loop in midbrain-hindbrain boundary development is revealed through analysis of the zebrafish pax2.1 promoter in transgenic lines. Picker, A., Scholpp, S., Böhli, H., Takeda, H., Brand, M. Development (2002) [Pubmed]
  8. Zebrafish no isthmus reveals a role for pax2.1 in tubule differentiation and patterning events in the pronephric primordia. Majumdar, A., Lun, K., Brand, M., Drummond, I.A. Development (2000) [Pubmed]
  9. Zebrafish hhex, nk2.1a, and pax2.1 regulate thyroid growth and differentiation downstream of Nodal-dependent transcription factors. Elsalini, O.A., von Gartzen, J., Cramer, M., Rohr, K.B. Dev. Biol. (2003) [Pubmed]
  10. Mutations in zebrafish genes affecting the formation of the boundary between midbrain and hindbrain. Brand, M., Heisenberg, C.P., Jiang, Y.J., Beuchle, D., Lun, K., Furutani-Seiki, M., Granato, M., Haffter, P., Hammerschmidt, M., Kane, D.A., Kelsh, R.N., Mullins, M.C., Odenthal, J., van Eeden, F.J., Nüsslein-Volhard, C. Development (1996) [Pubmed]
  11. Midline signalling is required for Pax gene regulation and patterning of the eyes. Macdonald, R., Barth, K.A., Xu, Q., Holder, N., Mikkola, I., Wilson, S.W. Development (1995) [Pubmed]
  12. The Pax protein Noi is required for commissural axon pathway formation in the rostral forebrain. Macdonald, R., Scholes, J., Strähle, U., Brennan, C., Holder, N., Brand, M., Wilson, S.W. Development (1997) [Pubmed]
  13. Zebrafish aussicht mutant embryos exhibit widespread overexpression of ace (fgf8) and coincident defects in CNS development. Heisenberg, C.P., Brennan, C., Wilson, S.W. Development (1999) [Pubmed]
  14. The deltaA gene of zebrafish mediates lateral inhibition of hair cells in the inner ear and is regulated by pax2.1. Riley, B.B., Chiang, M., Farmer, L., Heck, R. Development (1999) [Pubmed]
  15. spiel ohne grenzen/pou2 is required during establishment of the zebrafish midbrain-hindbrain boundary organizer. Belting, H.G., Hauptmann, G., Meyer, D., Abdelilah-Seyfried, S., Chitnis, A., Eschbach, C., Söll, I., Thisse, C., Thisse, B., Artinger, K.B., Lunde, K., Driever, W. Development (2001) [Pubmed]
  16. Zebrafish pax5 regulates development of the utricular macula and vestibular function. Kwak, S.J., Vemaraju, S., Moorman, S.J., Zeddies, D., Popper, A.N., Riley, B.B. Dev. Dyn. (2006) [Pubmed]
  17. Initial specification of the epibranchial placode in zebrafish embryos depends on the fibroblast growth factor signal. Nikaido, M., Doi, K., Shimizu, T., Hibi, M., Kikuchi, Y., Yamasu, K. Dev. Dyn. (2007) [Pubmed]
  18. Tracing of her5 progeny in zebrafish transgenics reveals the dynamics of midbrain-hindbrain neurogenesis and maintenance. Tallafuss, A., Bally-Cuif, L. Development (2003) [Pubmed]
  19. Role of two genes encoding PACAP in early brain development in zebrafish. Wu, S., Adams, B.A., Fradinger, E.A., Sherwood, N.M. Ann. N. Y. Acad. Sci. (2006) [Pubmed]
 
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