Developmental Signals - Pax

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Introduction

Phylogenetic tree of Pax genes[1]

The name derived from Drosophila gene "paired" (prd) with a box (homeodomain) domain. A transcription factor of the helix-turn-helix structural family, DNA binding, and activating gene expression. In human, there are nine member proteins from Pax1 to Pax9.


Pax6 has been identified as regulating development of the central nervous system, eyes, nose, pancreas and pituitary gland.


Developmental Functions: Mesoderm | Neural | Vision | Pancreas | Pituitary| Thymus

Factor Links: hCG | BMP | Sonic hedgehog | Homeobox | FGF | Nanog | Notch | Fox | Pax | Retinoic acid | Sox | Tbx | TGF-beta | VEGF | Wnt | Hippo | Category:Molecular

Some Recent Findings

  • Review - Pax genes: regulators of lineage specification and progenitor cell maintenance[2] "Pax genes encode a family of transcription factors that orchestrate complex processes of lineage determination in the developing embryo. Their key role is to specify and maintain progenitor cells through use of complex molecular mechanisms such as alternate RNA splice forms and gene activation or inhibition in conjunction with protein co-factors. The significance of Pax genes in development is highlighted by abnormalities that arise from the expression of mutant Pax genes. Here, we review the molecular functions of Pax genes during development and detail the regulatory mechanisms by which they specify and maintain progenitor cells across various tissue lineages."
  • Downstream genes of Pax6 in the developing rat hindbrain [3] "These results indicate that Unc5h1 and Cyp26b1 are novel candidates for target genes transactivated by Pax6. Furthermore, our results suggest the interesting possibility that Pax6 regulates anterior-posterior patterning of the hindbrain via activation of Cyp26b1, an enzyme that metabolizes retinoic acid."
More recent papers
Mark Hill.jpg
This table shows an automated computer PubMed search using the listed sub-heading term.
  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent


Search term: Development Pax

Peter Fabian, Iryna Kozmikova, Zbynek Kozmik, Chrysoula N Pantzartzi Pax2/5/8 and Pax6 alternative splicing events in basal chordates and vertebrates: a focus on paired box domain. Front Genet: 2015, 6;228 PMID: 26191073 Lei Shi, Bo Zhou, Pinghua Li, A P Schinckel, Tingting Liang, Han Wang, Huizhi Li, Lingling Fu, Qingpo Chu, Ruihua Huang MicroRNA-128 targets myostatin at coding domain sequence to regulate myoblasts in skeletal muscle development. Cell. Signal.: 2015; PMID: 25958325 Jau-Yu Liau, Jia-Huei Tsai, Yung-Ming Jeng, Kuan-Ting Kuo, Hsin-Yi Huang, Cher-Wei Liang, Ching-Yao Yang The Diagnostic Utility of PAX8 for Neuroendocrine Tumors: An Immunohistochemical Reappraisal. Appl. Immunohistochem. Mol. Morphol.: 2015; PMID: 25710581 Xinyu Yang, Chenguang Xi, Jie Jin, Liqun Zhou, Jinwei Su, Libo Liu, Yuli Liu Adult renal cell carcinoma with rhabdoid differentiation: incidence and clinicopathologic features in Chinese patients. Ann Diagn Pathol: 2015; PMID: 25708024 Sally A Moody, Anthony-Samuel LaMantia Transcriptional regulation of cranial sensory placode development. Curr. Top. Dev. Biol.: 2015, 111;301-50 PMID: 25662264

Transcription Factor

Pax and DNA interaction cartoon

Pax and DNA molecular interaction[2]


Mesoderm Development

Mesoderm Development and Pax cartoon

Mesoderm Development and Pax[2]


Neural Development

Mouse- early Pax8 and Pax2 expression[4]
  • Hoxd4 gene a direct target of Pax6[5]
    • mouse embryo - Hoxd4 expression in rhombomere 7 and the spinal cord is reduced to some extent in the Pax6 mutant
    • zebrafish embryo - double knockdown of pax6a and pax6b with MOs resulted in malformed rhombomere boundaries and an anteriorized hoxd4a expression border
  • Pax3 is expressed in the somite, neural tube, and neural crest.
  • Pax3 is required for enteric ganglia formation.[6]
  • Pax2 and Pax5 in midbrain and cerebellum development.[7]

Vision Development

Pax6 eye phenotypes.jpg

Pax6 mutation eye phenotypes[8]

Pancreas Development

  • Pax6 acts in endocrine development in the pancreas as a glucagon gene transactivator role in alpha (α) cell development.
  • Pax2 is also expressed in the pancreas.
  • Pax4 is a regulator of pancreatic beta cell development.[9]
Developmental Factors
  • Pdx1 - Pancreas/Duodenum Homeobox Protein 1 OMIM 600733
    • transcription (transactivator) factor binds the TAAT element in the promoter region of target genes, mainly those involved in pancreas development.
  • Ngn3 - Neurogenin3 OMIM 604882
    • basic helix-loop-helix transcription factor involved in the determination of neural precursor cells in the neuroectoderm.
  • NeuroD1 - Neurogenic Differentiation 1 OMIM 601724
    • a basic helix-loop-helix (bHLH) protein that acts as a transcription factors involved in determining cell type during development.
  • Arx - Aristaless-Related Homeobox, X-Linked OMIM 300382
    • homeobox protein that belongs to the Aristaless-related subset of the paired (Prd) class of homeodomain proteins.
  • Pax4 - Paired Box Gene 4 OMIM 167413
    • transcription factor containing a paired box domain.
  • Pax6 Paired Box Gene 6 OMIM 607108
    • transcription factor containing a paired box domain.
  • Nkx2.2 - NK2 Homeobox 2 OMIM 604612
    • homeobox (Hox) containing transcription factor contain a 60-amino acid evolutionarily conserved DNA-binding homeodomain.
  • Nkx6.1 - NK2 Homeobox 6.1 OMIM 602563
    • homeobox (Hox) containing transcription factor contain a 60-amino acid evolutionarily conserved DNA-binding homeodomain.
    • required for beta cells development and is completely conserved between rat, mouse, and human.
Molecular Development of Endocrine Pancreas Cells

Molecular Development of Endocrine Pancreas Cells[10]

Links: Endocrine Pancreas

Thymus Development

Pax1 mouse KO thymus size reduction and impaired thymocyte maturation.


Links: Thymus Pancreas

Structure

  • tissue-specific transcriptional regulators
  • contain a highly conserved DNA-binding domain with six alpha-helices (paired domain)
  • a complete or residual homeodomain.
  • 4 Groups: group I (Pax-1, 9), II (Pax-2, 5, 8), III (Pax-3, 7), and IV (Pax-4, 6)[11]

Mouse Expression

The following gallery is from a recent paper using a Pax7-cre/reporter mouse.[12]

Mouse palate gene expression 01.jpg

Mouse Palatal Shelf Wnt5a, Osr2 and Pax9 Expression.[13]

The following data is from a recent paper using a Pax9 reporter.[14]

Mouse Tongue Pax9 Expression in Different Taste Papillae
Mouse tongue Pax9 expression 03.jpg E13.5 Mouse Tongue Pax9 Expression in Different Taste Papillae
  • A. Drawing showing the localization of the circumvallate papilla (CVP), foliate papillae (FOP), and fungiform papillae (FUP) in the mouse tongue.
  • B. Whole mount X-Gal staining of a Pax9+/LacZ mouse tongue at embryonic day 13.5 (E13.5).

Note that expression is also seen in the mesenchyme adjacent to the developing FOP (arrowheads) and that the color reaction was stopped before epithelial staining began to obscure the mesenchymal expression domain.

B Scale bar 200 µm.

Mouse tongue Pax9 expression 02.jpg E13.5 -E18.5 Mouse Tongue Pax9 Expression in Different Taste Papillae

Pax9 immunostaining of taste papillae during development on cross sections (C–F; K–N) and horizontal sections of the tongue (G–J).

  • C–F Pax9 is expressed in the epithelium during CVP morphogenesis and is down-regulated in some regions of the trenches at E18.5 (arrowhead in F).
  • G–J In addition to the epithelium, Pax9 is also expressed in the mesenchyme during FOP development, while reduced Pax9 levels were observed in the trenches at E18.5 (arrowhead in J).
  • K–N In the anterior part of the tongue Pax9 is expressed in the FUP epithelium and in filiform papillae (FIP). Note that the expression is very weak or absent in the taste placodes (arrowheads).

Scale bars 50 µm.


Links: Mouse Development | Neural Crest Development | Taste Development

Abnormalities

Associated with defects in each Pax protein or their signaling pathway.

Pax2

  • renal-coloboma syndrome (RCS)


Links: Vision Abnormalities | Genetics Home Reference

Pax3

  • Waardenburg syndrome type 1 (WS1)
  • Waardenburg syndrome type 3 (WS3)
  • craniofacial-deafness-hand syndrome (CDHS)
  • rhabdomyosarcoma type 2 (RMS2)

Pax5

  • acute lymphoblastic leukemia

Pax6

A series of vision associated defects.

  • aniridia (AN)
  • Peters anomaly
  • ectopia pupillae
  • foveal hypoplasia
  • autosomal dominant keratitis
  • ocular coloboma
  • coloboma of optic nerve
  • bilateral optic nerve hypoplasia
  • aniridia cerebellar ataxia and mental deficiency (ACAMD)
Links: Vision Abnormalities

Pax7

  • rhabdomyosarcoma type 2 (RMS2)

Pax8

  • congenital hypothyroidism non-goitrous type 2 (CHNG2)
Links:Thyroid Abnormalities

References

  1. H Sun, A Rodin, Y Zhou, D P Dickinson, D E Harper, D Hewett-Emmett, W H Li Evolution of paired domains: isolation and sequencing of jellyfish and hydra Pax genes related to Pax-5 and Pax-6. Proc. Natl. Acad. Sci. U.S.A.: 1997, 94(10);5156-61 PMID: 9144207
  2. 2.0 2.1 2.2 Judith A Blake, Melanie R Ziman Pax genes: regulators of lineage specification and progenitor cell maintenance. Development: 2014, 141(4);737-51 PMID: 24496612 | Development
  3. Keiko Numayama-Tsuruta, Yoko Arai, Masanori Takahashi, Makiko Sasaki-Hoshino, Nobuo Funatsu, Shun Nakamura, Noriko Osumi Downstream genes of Pax6 revealed by comprehensive transcriptome profiling in the developing rat hindbrain. BMC Dev. Biol.: 2010, 10;6 PMID: 20082710 | BMC Dev. Biol.
  4. Maxime Bouchard, Dominique de Caprona, Meinrad Busslinger, Pinxian Xu, Bernd Fritzsch Pax2 and Pax8 cooperate in mouse inner ear morphogenesis and innervation. BMC Dev. Biol.: 2010, 10;89 PMID: 20727173 | PMC2939565 | BMC Dev Biol.
  5. Christof Nolte, Mojgan Rastegar, Angel Amores, Maxime Bouchard, David Grote, Richard Maas, Erzsebet Nagy Kovacs, John Postlethwait, Isabel Rambaldi, Sheldon Rowan, Yi-Lin Yan, Feng Zhang, Mark Featherstone Stereospecificity and PAX6 function direct Hoxd4 neural enhancer activity along the antero-posterior axis. Dev. Biol.: 2006, 299(2);582-93 PMID: 17010333
  6. D Lang, F Chen, R Milewski, J Li, M M Lu, J A Epstein Pax3 is required for enteric ganglia formation and functions with Sox10 to modulate expression of c-ret. J. Clin. Invest.: 2000, 106(8);963-71 PMID: 11032856
  7. M Schwarz, G Alvarez-Bolado, P Urbánek, M Busslinger, P Gruss Conserved biological function between Pax-2 and Pax-5 in midbrain and cerebellum development: evidence from targeted mutations. Proc. Natl. Acad. Sci. U.S.A.: 1997, 94(26);14518-23 PMID: 9405645
  8. Nicole L Washington, Melissa A Haendel, Christopher J Mungall, Michael Ashburner, Monte Westerfield, Suzanna E Lewis Linking human diseases to animal models using ontology-based phenotype annotation. PLoS Biol.: 2009, 7(11);e1000247 PMID: 19956802 | PLoS Biol.
  9. Beatriz Sosa-Pineda The gene Pax4 is an essential regulator of pancreatic beta-cell development. Mol. Cells: 2004, 18(3);289-94 PMID: 15650323
  10. Yaron Suissa, Judith Magenheim, Miri Stolovich-Rain, Ayat Hija, Patrick Collombat, Ahmed Mansouri, Lori Sussel, Beatriz Sosa-Pineda, Kyle McCracken, James M Wells, R Scott Heller, Yuval Dor, Benjamin Glaser Gastrin: a distinct fate of neurogenin3 positive progenitor cells in the embryonic pancreas. PLoS ONE: 2013, 8(8);e70397 PMID: 23940571 | PLoS One.
  11. K A Balczarek, Z C Lai, S Kumar Evolution of functional diversification of the paired box (Pax) DNA-binding domains. Mol. Biol. Evol.: 1997, 14(8);829-42 PMID: 9254921
  12. Barbara Murdoch, Casey DelConte, Martín I García-Castro Pax7 lineage contributions to the mammalian neural crest. PLoS ONE: 2012, 7(7);e41089 PMID: 22848431 | PMC2634972 | PLoS One.
  13. Asma Almaidhan, Jeffry Cesario, Andre Landin Malt, Yangu Zhao, Neeti Sharma, Veronica Choi, Juhee Jeong Neural crest-specific deletion of Ldb1 leads to cleft secondary palate with impaired palatal shelf elevation. BMC Dev. Biol.: 2014, 14;3 PMID: 24433583 | BMC Dev Biol.
  14. Ralf Kist, Michelle Watson, Moira Crosier, Max Robinson, Jennifer Fuchs, Julia Reichelt, Heiko Peters The formation of endoderm-derived taste sensory organs requires a pax9-dependent expansion of embryonic taste bud progenitor cells. PLoS Genet.: 2014, 10(10);e1004709 PMID: 25299669 | PLoS Genet.

Search Bookshelf Pax

Reviews

Margaret Buckingham, Frédéric Relaix The role of Pax genes in the development of tissues and organs: Pax3 and Pax7 regulate muscle progenitor cell functions. Annu. Rev. Cell Dev. Biol.: 2007, 23;645-73 PMID: 17506689

A Mansouri, G Goudreau, P Gruss Pax genes and their role in organogenesis. Cancer Res.: 1999, 59(7 Suppl);1707s-1709s; discussion 1709s-1710s PMID: 10197584


Search Pubmed

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http://www.ncbi.nlm.nih.gov/omim

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Cite this page: Hill, M.A. (2015) Embryology Developmental Signals - Pax. Retrieved July 30, 2015, from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Signals_-_Pax

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© Dr Mark Hill 2015, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G