Developmental Signals - Pax

Embryology - 2 Dec 2023        Expand to Translate
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Introduction

Phylogenetic tree of Pax genes

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

Some Recent Findings

Anti-EDAR Agonist Antibody Therapy Resolves Palate Defects in Pax9-/- Mice "Here, we use the well-characterized model of the Pax9-/- mouse, which displays a consistent phenotype of a secondary cleft palate, to test a novel therapeutic. Specifically, we demonstrate that the controlled intravenous delivery of a novel mouse monoclonal antibody replacement therapy, which acts as an agonist for the ectodysplasin (Eda) pathway, can resolve cleft palate defects in Pax9-/- embryos in utero. Such pharmacological interventions did not reverse the arrest in tooth, thymus, and parathyroid gland development, suggesting that the relationship of Pax9 to the Eda/Edar pathway is both unique and essential for palatogenesis. Expression analyses and unbiased gene expression profiling studies offer a molecular explanation for the resolution of palatal defects, showing that Eda and Edar-related genes are expressed in normal palatal tissues and that the Eda/Edar signaling pathway is downstream of Pax9 in palatogenesis." palate The axolotl genome and the evolution of key tissue formation regulators "Salamanders serve as important tetrapod models for developmental, regeneration and evolutionary studies. An extensive molecular toolkit makes the Mexican axolotl (Ambystoma mexicanum) a key representative salamander for molecular investigations. Here we report the sequencing and assembly of the 32-gigabase-pair axolotl genome using an approach that combined long-read sequencing, optical mapping and development of a new genome assembler (MARVEL). We observed a size expansion of introns and intergenic regions, largely attributable to multiplication of long terminal repeat retroelements. We provide evidence that intron size in developmental genes is under constraint and that species-restricted genes may contribute to limb regeneration. The axolotl genome assembly does not contain the essential developmental gene Pax3. However, mutation of the axolotl Pax3 paralogue Pax7 resulted in an axolotl phenotype that was similar to those seen in Pax3-/- and Pax7-/- mutant mice." The Pax gene family: Highlights from cephalopods "Pax genes play important roles in Metazoan development. Their evolution has been extensively studied but Lophotrochozoa are usually omitted. We addressed the question of Pax paralog diversity in Lophotrochozoa by a thorough review of available databases. The existence of six Pax families (Pax1/9, Pax2/5/8, Pax3/7, Pax4/6, Paxβ, PoxNeuro) was confirmed and the lophotrochozoan Paxβ subfamily was further characterized. Contrary to the pattern reported in chordates, the Pax2/5/8 family is devoid of homeodomain in Lophotrochozoa. Expression patterns of the three main pax classes (pax2/5/8, pax3/7, pax4/6) during Sepia officinalis development showed that Pax roles taken as ancestral and common in metazoans are modified in S. officinalis, most likely due to either the morphological specificities of cephalopods or to their direct development. Some expected expression patterns were missing (e.g. pax6 in the developing retina), and some expressions in unexpected tissues have been found (e.g. pax2/5/8 in dermal tissue and in gills). This study underlines the diversity and functional plasticity of Pax genes and illustrates the difficulty of using probable gene homology as strict indicator of homology between biological structures." Review - Pax genes: regulators of lineage specification and progenitor cell maintenance "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 "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

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Human PAX Family

Table - Human Pax Family
Approved Symbol	Approved Name	Previous Symbols	Synonyms	Chromosome
PAX1	paired box 1			20p11.22
PAX2	paired box 2			10q24.31
PAX3	paired box 3	WS1	HUP2	2q36.1
PAX4	paired box 4		MODY9	7q32.1
PAX5	paired box 5		BSAP	9p13.2
PAX6	paired box 6	AN2	"D11S812E, AN, WAGR"	11p13
PAX7	paired box 7		Hup1	1p36.13
PAX8	paired box 8			2q14.1
PAX9	paired box 9			14q13.3
Links: Developmental Signals - Pax | OMIM Pax1 | HGNC | Bmp Family | Fgf Family | Pax Family | Sox Family | Tbx Family

Human PAX Family

Table - Human Pax Family Approved Symbol Approved Name Previous Symbols Synonyms Chromosome PAX1 paired box 1 20p11.22 PAX2 paired box 2 10q24.31 PAX3 paired box 3 WS1 HUP2 2q36.1 PAX4 paired box 4 MODY9 7q32.1 PAX5 paired box 5 BSAP 9p13.2 PAX6 paired box 6 AN2 "D11S812E, AN, WAGR" 11p13 PAX7 paired box 7 Hup1 1p36.13 PAX8 paired box 8 2q14.1 PAX9 paired box 9 14q13.3     Links: Developmental Signals - Pax | OMIM Pax1 | HGNC | Bmp Family | Fgf Family | Pax Family | Sox Family | Tbx Family

Transcription Factor

Pax and DNA molecular interaction

Mesoderm Development

Mesoderm Development and Pax

Neural Development

Mouse- early Pax8 and Pax2 expression

• Hoxd4 gene a direct target of Pax6
  • 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.
• Pax2 and Pax5 in midbrain and cerebellum development.

Vision Development

Pax6 mutation eye phenotypes

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.

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

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)

Mouse Expression

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

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  E7.5 E8.5 neural fold

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  E9.5 Pax7 heart

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  E11.5 Trunk neural crest 1

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  E11.5 Trunk neural crest 2

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  E15.5 Pax7 limb

Mouse Palatal Shelf Wnt5a, Osr2 and Pax9 Expression.

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

Mouse Tongue Pax9 Expression in Different Taste Papillae
	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.
	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

Search Bookshelf Pax

Reviews

Buckingham M & Relaix F. (2007). 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. , 23, 645-73. PMID: 17506689 DOI.

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

Search Pubmed

Search Pubmed Now: Pax

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

External Links

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• OMIM - Pax6

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Cite this page: Hill, M.A. (2023, December 2) Embryology Developmental Signals - Pax. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Signals_-_Pax

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© Dr Mark Hill 2023, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G