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{{Infobox_gene}}'''PAX3''' is a gene within the PAX family, a group of transcription factors consisting of proteins binding to DNA sequences to control gene transcription. Pax3 is important in embryonic development because Pax3 is active in [[Neural Crest Cells|neural crest cells]]. In conjunction with [[MSX1|Msx1]], Pax3 guides the expression of [[SNAI1|Snail1]] and [[SNAI2|Snail2]] down-regulating adhesion molecules. This allows neural crest cells to become [[mesenchymal cells]] that migrate throughout the body and become bones and muscles around the face, the [[parasympathetic nervous system]], and other structural components. As a result, mutations within Pax3 generally result in developmental malformations because neural crest cells cannot move to the necessary parts of the body to complete their function. Craniofacial-deafness-hand syndrome is an example of an [[autosomal dominant]] disease resulting from a missense mutation in [[exon]]2 of Pax3. This mutation results in replacing the amino acid [[asparagine]] with [[lysine]], inhibiting the Pax3 protein from binding to the necessary [[DNA]].<ref name=":0">{{Cite journal|last=Sommer|first=Annemarie|last2=Bartholomew|first2=Dennis W.|date=2003-11-15|title=Craniofacial-deafness-hand syndrome revisited|url=https://www.ncbi.nlm.nih.gov/pubmed/14556253|journal=American Journal of Medical Genetics. Part A|volume=123A|issue=1|pages=91–94|doi=10.1002/ajmg.a.20501|issn=1552-4825|pmid=14556253}}</ref><ref>{{Cite journal|last=Asher|first=J. H.|last2=Sommer|first2=A.|last3=Morell|first3=R.|last4=Friedman|first4=T. B.|date=1996-01-01|title=Missense mutation in the paired domain of PAX3 causes craniofacial-deafness-hand syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8664898|journal=Human Mutation|volume=7|issue=1|pages=30–35|doi=10.1002/(SICI)1098-1004(1996)7:1<30::AID-HUMU4>3.0.CO;2-T|issn=1059-7794|pmid=8664898}}</ref> Craniofacial-deafness-hand syndrome has distinctive symptoms, such as an underdeveloped nasal bone, a small mouth and upper-jaw, pursed lips, and wide spaced eyes with narrowed eye openings. [[Hearing loss]] and deformities in hand muscles are common. Hand abnormalities typically present themselves as angled and bent fingers. Depending on the severity, finger and hand movement can be limited. Despite these physical malformations, individuals have normal intelligence and an active life.<ref name=":0" /><ref>{{Cite journal|last=Sommer|first=A.|last2=Young-Wee|first2=T.|last3=Frye|first3=T.|date=1983-05-01|title=Previously undescribed syndrome of craniofacial, hand anomalies, and sensorineural deafness|url=https://www.ncbi.nlm.nih.gov/pubmed/6859126|journal=American Journal of Medical Genetics|volume=15|issue=1|pages=71–77|doi=10.1002/ajmg.1320150109|issn=0148-7299|pmid=6859126}}</ref> Diagnosis involves [[genotyping]] and collaborative efforts from orthopedists, pediatricians, and ophthalmologists. While there are knockout models developed for Pax3, they focused on cancers rather than this syndrome.
{{Infobox_gene}}
The '''PAX3''' (paired box gene 3) [[gene]] encodes a member of the paired box or [[Pax genes|PAX]] family of [[transcription factor]]s.<ref>{{cite journal | vauthors = Stuart ET, Kioussi C, Gruss P | title = Mammalian Pax genes | journal = Annual Review of Genetics | volume = 28 | pages = 219–36 | date = 1994 | pmid = 7893124 | doi = 10.1146/annurev.ge.28.120194.001251 | department = review }}</ref> The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in a subfamily along with the highly homologous human [[PAX7]] and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 [[exon]]s within a 100 kb region.


'''PAX3''' is a gene that belongs to the [[Pax genes|paired box]] (PAX) family of [[transcription factor]]s.<ref name="entrez_PAX3_human" /> This gene was formerly known as '''splotch'''.<ref name="entrez_PAX3_mouse">{{cite web | title = Entrez Gene: Pax3 paired box gene 3 [Mus musculus] | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=18505| accessdate = }}</ref> PAX3 has been identified with ear, eye and facial development.<ref>http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1002932</ref> Mutations in it can cause [[Waardenburg syndrome]] types 1 and 3. It is expressed in early embryonic phases in dermatomyotome of [[paraxial mesoderm]] which it helps to demarcate. In that way PAX3 contributes to early striated muscle development since all [[myoblast]]s are derived from dermatomyotome of paraxial mesoderm.
== Transcript splicing ==
[[Alternative splicing]] and processing generates multiple PAX3 [[isoforms]] that have been detected at the mRNA level.<ref>{{cite journal | vauthors = Wang Q, Fang WH, Krupinski J, Kumar S, Slevin M, Kumar P | title = Pax genes in embryogenesis and oncogenesis | journal = Journal of Cellular and Molecular Medicine | volume = 12 | issue = 6A | pages = 2281–94 | date = December 2008 | pmid = 18627422 | doi = 10.1111/j.1582-4934.2008.00427.x | department = review }}</ref> PAX3e is the longest isoform and consists of 10 exons that encode a 505 amino acid protein. In other mammalian species, including mouse, the longest mRNAs correspond to the human PAX3c and PAX3d isoforms, which consist of the first 8 or 9 exons of the PAX3 gene, respectively. Shorter PAX3 isoforms include mRNAs that skip exon 8 (PAX3g and PAX3h) and mRNAs containing 4 or 5 exons (PAX3a and PAX3b). In limited studies comparing isoform expression, PAX3d is expressed at the highest levels. From a functional standpoint, PAX3c, PAX3d, and PAX3h stimulate activities such as cell growth whereas PAX3e and PAX3g inhibit these activities, and PAX3a and PAX3b show no activity or inhibit these endpoints.


[[Alternative splicing]] results in transcripts encoding isoforms with different [[C-terminus|C-termini]].<ref name ="entrez_PAX3_human">{{cite web | title = Entrez Gene: PAX3 paired box 3 [Homo sapiens] | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5077| accessdate = }}</ref>
A common alternative splice affecting the PAX3 mRNA involves the sequence CAG at the 5’ end of exon 3.<ref>{{cite journal | vauthors = Vogan KJ, Underhill DA, Gros P | title = An alternative splicing event in the Pax-3 paired domain identifies the linker region as a key determinant of paired domain DNA-binding activity | journal = Molecular and Cellular Biology | volume = 16 | issue = 12 | pages = 6677–86 | date = December 1996 | pmid = 8943322 | pmc = 231670 | department = primary }}</ref> This splice either includes or excludes these three bases, thus resulting in the presence or absence of a glutamine residue in the paired box motif. Limited sequencing studies of full-length human cDNAs identified this splicing event as a variant of the PAX3d isoform, and this spliced isoform has been separately termed the PAX3i isoform. The Q+ and Q- isoforms of PAX3 are generally co-expressed in cells. At the functional level, the Q+ isoform shows similar or less DNA binding and transcriptional activation than the Q- isoform.


==Role in rhabdomyosarcoma==
== Protein structure and function ==
A PAX3/[[FOXO1A|FKHR]] [[fusion gene]] is often associated with the alveolar type of [[rhabdomyosarcoma]],<ref>{{cite journal |vauthors=Begum S, Emami N, Emani N, etal |title=Cell-type-specific regulation of distinct sets of gene targets by Pax3 and Pax3/FKHR |journal=Oncogene |volume=24 |issue=11 |pages=1860–72 |date=March 2005 |pmid=15688035 |doi=10.1038/sj.onc.1208315 |url=}}</ref> a kind of cancer arisen from striated muscle cells. Translocation between chromosomes 2 & 13 produce fusion protein PAX3/FKHR which serves as a tumor marker in this type of RMS.Also in ARMS expressing PAX3/FKHR increased risk of metastasis to bone marrow and hence increased rate of failure and death were seen.
[[File:PAX3.hg38.fig.new.7.tif|thumb|left|'''Structure of the ''PAX3'' gene, mRNA and protein.''' The exons in the DNA and mRNA diagrams are numbered, and a horizontal arrow in the DNA diagram shows the promoter and direction of transcription. The start and stop codons are shown in the mRNA diagram by the vertical arrows. Conserved regions are indicated by open boxes in the protein diagram, and functional domains are indicated as thick horizontal lines above the protein diagram. Representative sizes are shown by the thin horizontal line segments in the DNA, mRNA and protein diagrams. Abbreviations: PB, paired box domain; HD, homeodomain; PST, proline-, serine- and threonine-rich region; DBD, DNA binding domain; TAD, transcription activation domain.|314x314px]]
PAX3 encodes a transcription factor with an N-terminal DNA binding domain consisting of a [[Paired box domain|paired box]] (PD) encoded by exons 2, 3, and 4, and an octapeptide and complete [[Homeobox|homeodomain]] (HD) encoded by exons 5 and 6.<ref>{{cite journal | vauthors = Baldwin CT, Hoth CF, Macina RA, Milunsky A | title = Mutations in PAX3 that cause Waardenburg syndrome type I: ten new mutations and review of the literature | journal = American Journal of Medical Genetics | volume = 58 | issue = 2 | pages = 115–22 | date = August 1995 | pmid = 8533800 | doi = 10.1002/ajmg.1320580205 | department = review }}</ref> In addition, the PAX3 protein has a C-terminal transcriptional activation domain encoded by exons 7 and 8. The highly conserved PD consists of a 128 amino acid region that binds to DNA sequences related to the TCACGC/G motif.<ref>{{cite journal | vauthors = Jun S, Desplan C | title = Cooperative interactions between paired domain and homeodomain | journal = Development | volume = 122 | issue = 9 | pages = 2639–50 | date = September 1996 | pmid = 8787739 | department = primary }}</ref> The HD motif usually consists of 60 amino acids and binds to sequences containing a TAAT core motif.<ref>{{cite journal | vauthors = Wilson D, Sheng G, Lecuit T, Dostatni N, Desplan C | title = Cooperative dimerization of paired class homeo domains on DNA | journal = Genes & Development | volume = 7 | issue = 11 | pages = 2120–34 | date = November 1993 | pmid = 7901121 | department = primary }}</ref> The combination of these two DNA binding domains enable the PAX3 protein to recognize longer sequences containing PD and HD binding sites.<ref>{{cite journal | vauthors = Phelan SA, Loeken MR | title = Identification of a new binding motif for the paired domain of Pax-3 and unusual characteristics of spacing of bipartite recognition elements on binding and transcription activation | journal = The Journal of Biological Chemistry | volume = 273 | issue = 30 | pages = 19153–9 | date = July 1998 | pmid = 9668101 | doi = 10.1074/jbc.273.30.19153 | department = primary }}</ref> In the C-terminus of PAX3, there is a proline, serine and threonine (PST)-rich region measuring 78 amino acids that functions to stimulate transcriptional activity.<ref>{{cite journal | vauthors = Bennicelli JL, Fredericks WJ, Wilson RB, Rauscher FJ, Barr FG | title = Wild type PAX3 protein and the PAX3-FKHR fusion protein of alveolar rhabdomyosarcoma contain potent, structurally distinct transcriptional activation domains | journal = Oncogene | volume = 11 | issue = 1 | pages = 119–30 | date = July 1995 | pmid = 7624119 | department = primary }}</ref> There are also transcriptional repression domains in the HD and N-terminal region (including the first half of the PD) that repress the C-terminal transcriptional activation domain.<ref name="Bennicelli_1996">{{cite journal | vauthors = Bennicelli JL, Edwards RH, Barr FG | title = Mechanism for transcriptional gain of function resulting from chromosomal translocation in alveolar rhabdomyosarcoma | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 11 | pages = 5455–9 | date = May 1996 | pmid = 8643596 | pmc = 39267 | department = primary }}</ref>


==Interactions==
PAX3 functions as a transcriptional activator for most target genes, but also may repress a smaller subset of target genes.<ref>{{cite journal | vauthors = Mayanil CS, George D, Freilich L, Miljan EJ, Mania-Farnell B, McLone DG, Bremer EG | title = Microarray analysis detects novel Pax3 downstream target genes | journal = The Journal of Biological Chemistry | volume = 276 | issue = 52 | pages = 49299–309 | date = December 2001 | pmid = 11590174 | doi = 10.1074/jbc.M107933200 | department = primary }}</ref> These expression changes are effected through binding of PAX3 to specific recognition sites, which are situated in various genomic locations.<ref>{{cite journal | vauthors = Soleimani VD, Punch VG, Kawabe Y, Jones AE, Palidwor GA, Porter CJ, Cross JW, Carvajal JJ, Kockx CE, van IJcken WF, Perkins TJ, Rigby PW, Grosveld F, Rudnicki MA | title = Transcriptional dominance of Pax7 in adult myogenesis is due to high-affinity recognition of homeodomain motifs | journal = Developmental Cell | volume = 22 | issue = 6 | pages = 1208–20 | date = June 2012 | pmid = 22609161 | doi = 10.1016/j.devcel.2012.03.014 | department = primary }}</ref> Some binding sites are located in or near target genes, such as the 5’ promoter, first intron and 3’ untranslated region. A substantial number of PAX3 binding sites are located at larger distances upstream and downstream of target genes. Among the PAX3 target genes, there is one group associated with muscle development and a second group associated with neural and melanocyte development. The proteins encoded by these target genes regulate various functional activities in these lineages, including differentiation, proliferation, migration, adhesion, and apoptosis.
PAX3 has been shown to [[Protein-protein interaction|interact]] with [[MEOX1]],<ref name="pmid11423130">{{cite journal | vauthors = Stamataki D, Kastrinaki M, Mankoo BS, Pachnis V, Karagogeos D | title = Homeodomain proteins Mox1 and Mox2 associate with Pax1 and Pax3 transcription factors | journal = FEBS Lett. | volume = 499 | issue = 3 | pages = 274–8 |date=June 2001 | pmid = 11423130 | doi = 10.1016/S0014-5793(01)02556-X | url = | issn = }}</ref> [[MEOX2]]<ref name=pmid11423130/> and [[SOX10]]<ref name="pmid12668617">{{cite journal | vauthors = Lang D, Epstein JA | title = Sox10 and Pax3 physically interact to mediate activation of a conserved c-RET enhancer | journal = Hum. Mol. Genet. | volume = 12 | issue = 8 | pages = 937–45 |date=April 2003 | pmid = 12668617 | doi = 10.1093/hmg/ddg107 | url = | issn = }}</ref><ref name="pmid10942418">{{cite journal | vauthors = Bondurand N, Pingault V, Goerich DE, Lemort N, Sock E, Le Caignec C, Wegner M, Goossens M | title = Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome | journal = Hum. Mol. Genet. | volume = 9 | issue = 13 | pages = 1907–17 |date=August 2000 | pmid = 10942418 | doi = 10.1093/hmg/9.13.1907 | url = | issn = }}</ref> as well as [[phosphatidylcholine transfer protein]] (PCTP).<ref>{{cite journal | vauthors = Kanno K, Wu MK, Agate DA, Fanelli BK, Wagle N, Scapa EF, Ukomadu C, Cohen DE | title = Interacting proteins dictate function of the minimal START domain phosphatidylcholine transfer protein/StarD2. | journal = J. Biol. Chem. | volume = 282 | issue = 42 | pages = 30728–36 |date=October 2007 | pmid = 17704541 | doi = 10.1074/jbc.M703745200 | url = | issn = }}</ref> PAX3 has an important relationship with c-met in [[myogenesis]]; if PAX3 is mutated, c-met expression may be inhibited or prevented altogether resulting in a lack of lateral migration.


==References==
PAX3 interacts with other nuclear proteins, which modulate PAX3 transcriptional activity. Dimerization of PAX3 with another PAX3 molecule or a PAX7 molecule enables binding to a palindromic HD binding site (TAATCAATTA).<ref>{{cite journal | vauthors = Schäfer BW, Czerny T, Bernasconi M, Genini M, Busslinger M | title = Molecular cloning and characterization of a human PAX-7 cDNA expressed in normal and neoplastic myocytes | journal = Nucleic Acids Research | volume = 22 | issue = 22 | pages = 4574–82 | date = November 1994 | pmid = 7527137 | department = primary }}</ref> Interaction of PAX3 with other transcription factors (such as SOX10) or chromatin factors (such as PAX3/7BP) enables synergistic activation of PAX3 target genes.<ref>{{cite journal | vauthors = Lang D, Epstein JA | title = Sox10 and Pax3 physically interact to mediate activation of a conserved c-RET enhancer | journal = Human Molecular Genetics | volume = 12 | issue = 8 | pages = 937–45 | date = April 2003 | pmid = 12668617 | department = primary }}</ref><ref>{{cite journal | vauthors = Diao Y, Guo X, Li Y, Sun K, Lu L, Jiang L, Fu X, Zhu H, Sun H, Wang H, Wu Z | title = Pax3/7BP is a Pax7- and Pax3-binding protein that regulates the proliferation of muscle precursor cells by an epigenetic mechanism | journal = Cell Stem Cell | volume = 11 | issue = 2 | pages = 231–41 | date = August 2012 | pmid = 22862948 | doi = 10.1016/j.stem.2012.05.022 | department = primary }}</ref> In contrast, binding of PAX3 to co-repressors, such as calmyrin, inhibits activation of PAX3 target genes.<ref>{{cite journal | vauthors = Hollenbach AD, McPherson CJ, Lagutina I, Grosveld G | title = The EF-hand calcium-binding protein calmyrin inhibits the transcriptional and DNA-binding activity of Pax3 | journal = Biochimica et Biophysica Acta | volume = 1574 | issue = 3 | pages = 321–8 | date = April 2002 | pmid = 11997098 | department = primary }}</ref> These co-repressors may function by altering chromatin structure at target genes, inhibiting PAX3 recognition of its DNA binding site or directly altering PAX3 transcriptional activity.
{{reflist}}


==Further reading==
Finally, PAX3 protein expression and function can be modulated by post-translational modifications. PAX3 can be phosphorylated at serines 201, 205 and 209 by kinases such as GSK3b, which in some settings will increase PAX3 protein stability.<ref>{{cite journal | vauthors = Dietz KN, Miller PJ, Iyengar AS, Loupe JM, Hollenbach AD | title = Identification of serines 201 and 209 as sites of Pax3 phosphorylation and the altered phosphorylation status of Pax3-FOXO1 during early myogenic differentiation | journal = The International Journal of Biochemistry & Cell Biology | volume = 43 | issue = 6 | pages = 936–45 | date = June 2011 | pmid = 21440083 | pmc = 3095663 | doi = 10.1016/j.biocel.2011.03.010 | department = primary }}</ref><ref>{{cite journal | vauthors = Kubic JD, Mascarenhas JB, Iizuka T, Wolfgeher D, Lang D | title = GSK-3 promotes cell survival, growth, and PAX3 levels in human melanoma cells | journal = Molecular Cancer Research | volume = 10 | issue = 8 | pages = 1065–76 | date = August 2012 | pmid = 22679108 | pmc = 3422428 | doi = 10.1158/1541-7786.MCR-11-0387 | department = primary }}</ref> In addition, PAX3 can also undergo ubiquitination and acetylation at lysines 437 and 475, which regulates protein stability and function.<ref>{{cite journal | vauthors = Boutet SC, Disatnik MH, Chan LS, Iori K, Rando TA | title = Regulation of Pax3 by proteasomal degradation of monoubiquitinated protein in skeletal muscle progenitors | journal = Cell | volume = 130 | issue = 2 | pages = 349–62 | date = July 2007 | pmid = 17662948 | doi = 10.1016/j.cell.2007.05.044 | department = primary }}</ref><ref>{{cite journal | vauthors = Ichi S, Boshnjaku V, Shen YW, Mania-Farnell B, Ahlgren S, Sapru S, Mansukhani N, McLone DG, Tomita T, Mayanil CS | title = Role of Pax3 acetylation in the regulation of Hes1 and Neurog2 | journal = Molecular Biology of the Cell | volume = 22 | issue = 4 | pages = 503–12 | date = February 2011 | pmid = 21169561 | pmc = 3038648 | doi = 10.1091/mbc.E10-06-0541 | department = primary }}</ref>
{{refbegin|35em}}
 
*{{cite journal  | vauthors=Moase CE, Trasler DG |title=Splotch locus mouse mutants: models for neural tube defects and Waardenburg syndrome type I in humans. |journal=J. Med. Genet. |volume=29 |issue= 3 |pages= 145–51 |year= 1992 |pmid= 1552554 |doi=10.1136/jmg.29.3.145  | pmc=1015886  }}
'''Table 1. Representative PAX3 transcriptional target genes.'''
*{{cite journal | vauthors=Baldwin CT, Hoth CF, Macina RA, Milunsky A |title=Mutations in PAX3 that cause Waardenburg syndrome type I: ten new mutations and review of the literature. |journal=Am. J. Med. Genet. |volume=58 |issue= 2 |pages= 115–22 |year= 1996 |pmid= 8533800 |doi= 10.1002/ajmg.1320580205 }}
{| class="wikitable"
*{{cite journal | vauthors=Blake J, Ziman MR |title=Aberrant PAX3 and PAX7 expression. A link to the metastatic potential of embryonal rhabdomyosarcoma and cutaneous malignant melanoma? |journal=Histol. Histopathol. |volume=18 |issue= 2 |pages= 529–39 |year= 2003 |pmid= 12647804 |doi= }}
|'''Protein  category'''
*{{cite journal | author=Reddi KK |title=Human granulocyte ribonuclease. |journal=Biochem. Biophys. Res. Commun. |volume=68 |issue= 4 |pages= 1119–25 |year= 1976 |pmid= 5077 |doi=10.1016/0006-291X(76)90312-0  }}
|'''Name'''
*{{cite journal  |vauthors=Morell R, Friedman TB, Moeljopawiro S, etal |title=A frameshift mutation in the HuP2 paired domain of the probable human homolog of murine Pax-3 is responsible for Waardenburg syndrome type 1 in an Indonesian family. |journal=Hum. Mol. Genet. |volume=1 |issue= 4 |pages= 243–7 |year= 1993 |pmid= 1303193 |doi=10.1093/hmg/1.4.243  }}
|'''Phenotypic  Activity'''
*{{cite journal  | vauthors=Carezani-Gavin M, Clarren SK, Steege T |title=Waardenburg syndrome associated with meningomyelocele. |journal=Am. J. Med. Genet. |volume=42 |issue= 1 |pages= 135–6 |year= 1993 |pmid= 1308353 |doi= 10.1002/ajmg.1320420127 }}
|-
*{{cite journal  |vauthors=Tassabehji M, Read AP, Newton VE, etal |title=Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene. |journal=Nature |volume=355 |issue= 6361 |pages= 635–6 |year= 1992 |pmid= 1347148 |doi= 10.1038/355635a0 }}
|Cell adhesion molecule
*{{cite journal  |vauthors=Baldwin CT, Hoth CF, Amos JA, etal |title=An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome. |journal=Nature |volume=355 |issue= 6361 |pages= 637–8 |year= 1992 |pmid= 1347149 |doi= 10.1038/355637a0 }}
|''NRCAM''
*{{cite journal   |vauthors=Farrer LA, Grundfast KM, Amos J, etal |title=Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS consortium. |journal=Am. J. Hum. Genet. |volume=50 |issue= 5 |pages= 902–13 |year= 1992 |pmid= 1349198 |doi= | pmc=1682585  }}
|Intercellular adhesion
*{{cite journal  | vauthors=Sheffer R, Zlotogora J |title=Autosomal dominant inheritance of Klein-Waardenburg syndrome. |journal=Am. J. Med. Genet. |volume=42 |issue= 3 |pages= 320–2 |year= 1992 |pmid= 1536170 |doi= 10.1002/ajmg.1320420312 }}
|-
*{{cite journal   |vauthors=Burri M, Tromvoukis Y, Bopp D, etal |title=Conservation of the paired domain in metazoans and its structure in three isolated human genes. |journal=EMBO J. |volume=8 |issue= 4 |pages= 1183–90 |year= 1989 |pmid= 2501086 |doi= | pmc=400932  }}
|Chemokine receptor
*{{cite journal  | author=Newton VE |title=Waardenburg's syndrome: a comparison of biometric indices used to diagnose lateral displacement of the inner canthi. |journal=Scandinavian audiology |volume=18 |issue= 4 |pages= 221–3 |year= 1990 |pmid= 2609099 |doi=  10.3109/01050398909042198}}
|''CXCR4''
*{{cite journal  |vauthors=Newton CR, Graham A, Heptinstall LE, etal |title=Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). |journal=Nucleic Acids Res. |volume=17 |issue= 7 |pages= 2503–16 |year= 1989 |pmid= 2785681 |doi=10.1093/nar/17.7.2503  | pmc=317639  }}
|Motility
*{{cite journal  | vauthors=Sommer A, Young-Wee T, Frye T |title=Previously undescribed syndrome of craniofacial, hand anomalies, and sensorineural deafness. |journal=Am. J. Med. Genet. |volume=15 |issue= 1 |pages= 71–7 |year= 1983 |pmid= 6859126 |doi= 10.1002/ajmg.1320150109 }}
|-
*{{cite journal | vauthors=Goodman RM, Lewithal I, Solomon A, Klein D |title=Upper limb involvement in the Klein-Waardenburg syndrome. |journal=Am. J. Med. Genet. |volume=11 |issue= 4 |pages= 425–33 |year= 1982 |pmid= 7091186 |doi= 10.1002/ajmg.1320110407 }}
|Receptor tyrosine kinase
*{{cite journal | vauthors=Tsukamoto K, Nakamura Y, Niikawa N |title=Isolation of two isoforms of the PAX3 gene transcripts and their tissue-specific alternative expression in human adult tissues. |journal=Hum. Genet. |volume=93 |issue= 3 |pages= 270–4 |year= 1994 |pmid= 7545913 |doi=10.1007/BF00212021  }}
|''FGFR4''
*{{cite journal  |vauthors=Zlotogora J, Lerer I, Bar-David S, etal |title=Homozygosity for Waardenburg syndrome. |journal=Am. J. Hum. Genet. |volume=56 |issue= 5 |pages= 1173–8 |year= 1995 |pmid= 7726174 |doi= | pmc=1801439  }}
|Proliferation,  differentiation, migration
*{{cite journal | vauthors=Macina RA, Barr FG, Galili N, Riethman HC |title=Genomic organization of the human PAX3 gene: DNA sequence analysis of the region disrupted in alveolar rhabdomyosarcoma. |journal=Genomics |volume=26 |issue= 1 |pages= 1–8 |year= 1995 |pmid= 7782066 |doi=10.1016/0888-7543(95)80076-X  }}
|-
*{{cite journal  |vauthors=Lalwani AK, Brister JR, Fex J, etal |title=Further elucidation of the genomic structure of PAX3, and identification of two different point mutations within the PAX3 homeobox that cause Waardenburg syndrome type 1 in two families. |journal=Am. J. Hum. Genet. |volume=56 |issue= 1 |pages= 75–83 |year= 1995 |pmid= 7825605 |doi= | pmc=1801294  }}
|
|''MET''
|Proliferation, migration, survival
|-
|
|''RET''
|Proliferation, migration,  differentiation
|-
|Transcription factor
|''MITF''
|Differentiation, proliferation, survival
|-
|
|''MYF5''
|Differentiation
|-
|
|''MYOD1''
|Differentiation
|}
 
==Expression during development==
During development, one of the major lineages expressing Pax3 is the skeletal muscle lineage.<ref>{{cite journal | vauthors = Buckingham M, Relaix F | title = The role of Pax genes in the development of tissues and organs: Pax3 and Pax7 regulate muscle progenitor cell functions | journal = Annual Review of Cell and Developmental Biology | volume = 23 | pages = 645–73 | date = 2007 | pmid = 17506689 | doi = 10.1146/annurev.cellbio.23.090506.123438 | department = review }}</ref> Pax3 expression is first seen in the pre-somitic paraxial mesoderm, and then ultimately becomes restricted to the [[Somite|dermomyotome]], which forms from the dorsal region of the somites. To form skeletal muscle in central body segments, PAX3-expressing cells detach from the dermomyotome and then Pax3 expression is turned off as Myf5 and MyoD1 expression is activated. To form other skeletal muscles, Pax3-expressing cells detach from the dermomyotome and migrate to more distant sites, such as the limbs and diaphragm. A subset of these Pax3-expressing dermomyotome-derived cells also serves as an ongoing progenitor pool for skeletal muscle growth during fetal development. During later developmental stages, myogenic precursors expressing Pax3 and/or Pax7 form satellite cells within the skeletal muscle, which contribute to postnatal muscle growth and muscle regeneration. These adult satellite cells remain quiescent until injury occurs, and then are stimulated to divide and regenerate the injured muscle.
 
Pax3 is also involved in the development of the nervous system.<ref>{{cite journal | vauthors = Goulding MD, Chalepakis G, Deutsch U, Erselius JR, Gruss P | title = Pax-3, a novel murine DNA binding protein expressed during early neurogenesis | journal = The EMBO Journal | volume = 10 | issue = 5 | pages = 1135–47 | date = May 1991 | pmid = 2022185 | department = primary }}</ref> Expression of Pax3 is first detected in the dorsal region of the neural groove and, as this neural groove deepens to form the neural tube, Pax3 is expressed in the dorsal portion of the neural tube. As the neural tube enlarges, Pax3 expression is localized to proliferative cells in the inner ventricular zone and then this expression is turned off as these cells migrate to more superficial regions. Pax3 is expressed along the length of the neural tube and throughout much of the developing brain, and this expression is subsequently turned off during later developmental stages in a rostral to caudal direction.
 
During early development, Pax3 expression also occurs at the lateral and posterior margins of the neural plate, which is the region from which the [[neural crest]] arises.<ref>{{cite journal | vauthors = Monsoro-Burq AH | title = PAX transcription factors in neural crest development | journal = Seminars in Cell & Developmental Biology | volume = 44 | pages = 87–96 | date = August 2015 | pmid = 26410165 | doi = 10.1016/j.semcdb.2015.09.015 | department = review }}</ref> Pax3 is later expressed by various cell types and structures arising from the neural crest, such as melanoblasts, Schwann cell precursors, and dorsal root ganglia. In addition, Pax3-expressing cells derived from the neural crest contribute to the formation of other structures, such as the inner ear, mandible and maxilla.<ref>{{cite journal | vauthors = Wu M, Li J, Engleka KA, Zhou B, Lu MM, Plotkin JB, Epstein JA | title = Persistent expression of Pax3 in the neural crest causes cleft palate and defective osteogenesis in mice | journal = The Journal of Clinical Investigation | volume = 118 | issue = 6 | pages = 2076–87 | date = June 2008 | pmid = 18483623 | pmc = 2381747 | doi = 10.1172/JCI33715 | department = primary }}</ref>
 
== Germline mutations in disease ==
Germline mutations of the Pax3 gene cause the splotch phenotype in mice.<ref>{{cite journal | vauthors = Epstein DJ, Vekemans M, Gros P | title = Splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3 | journal = Cell | volume = 67 | issue = 4 | pages = 767–74 | date = November 1991 | pmid = 1682057 | department = primary }}</ref><ref>{{cite journal | vauthors = Tremblay P, Gruss P | title = Pax: genes for mice and men | journal = Pharmacology & Therapeutics | volume = 61 | issue = 1–2 | pages = 205–26 | date = 1994 | pmid = 7938171 | department = review }}</ref> At the molecular level, this phenotype is caused by point mutations or deletions that alter or abolish Pax3 transcriptional function. In the heterozygous state, the splotch phenotype is characterized by white patches in the belly, tail and feet. These white spots are attributed to localized deficiencies in pigment-forming melanocytes resulting from neural crest cell defects. In the homozygous state, these Pax3 mutations cause embryonic lethality, which is associated with prominent neural tube closure defects and abnormalities of neural crest-derived structures, such as melanocytes, dorsal root ganglia and enteric ganglia. Heart malformations also result from the loss of cardiac neural crest cells, which normally contribute to the cardiac outflow tract and innervation of the heart. Finally, limb musculature does not develop in the homozygotes and axial musculature demonstrates varying abnormalities. These myogenic effects are caused by increased cell death of myogenic precursors in the dermomyotome and diminished migration from the dermomyotome.
 
Germline mutations of the PAX3 gene occur in the human disease [[Waardenburg syndrome]],<ref>{{cite journal | vauthors = Baldwin CT, Hoth CF, Amos JA, da-Silva EO, Milunsky A | title = An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome | journal = Nature | volume = 355 | issue = 6361 | pages = 637–8 | date = February 1992 | pmid = 1347149 | doi = 10.1038/355637a0 | department = primary }}</ref> which consists of four autosomal dominant genetic disorders (WS1, WS2, WS3 and WS4).<ref>{{cite journal | vauthors = Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N | title = Review and update of mutations causing Waardenburg syndrome | journal = Human Mutation | volume = 31 | issue = 4 | pages = 391–406 | date = April 2010 | pmid = 20127975 | doi = 10.1002/humu.21211 | department = review | url = http://www.hal.inserm.fr/inserm-00483195/document }}</ref> Of the four subtypes, WS1 and WS3 are usually caused by PAX3 mutations. All four subtypes are characterized by hearing loss, eye abnormalities and pigmentation disorders. In addition, WS1 is frequently associated with a midfacial alteration called dystopia canthorum, while WS3 (Klein-Waardenburg syndrome) is frequently distinguished by musculoskeletal abnormalities affecting the upper limbs. Most WS1 cases are caused by heterozygous PAX3 mutations while WS3 is caused by either partial or total deletion of PAX3 and contiguous genes or by smaller PAX3 mutations in the heterozygous or homozygous state. These PAX3 mutations in WS1 and WS3 include missense, nonsense and splicing mutations; small insertions; and small or gross deletions. Though these changes are usually not recurrent, the mutations generally occur in exons 2 through 6 with exon 2 mutations being most common. As these exons encode the paired box and homeodomain, these mutations often affect DNA binding function.
 
== Mutations in human cancer ==
{{Medical citations needed|section|date=January 2018}}
[[Alveolar rhabdomyosarcoma]] (ARMS) is an aggressive soft tissue sarcoma that occurs in children and is usually characterized by a recurrent t(2;13)(q35;q14) chromosomal translocation.<ref>{{cite journal | vauthors = Barr FG | title = Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma | journal = Oncogene | volume = 20 | issue = 40 | pages = 5736–46 | date = September 2001 | pmid = 11607823 | doi = 10.1038/sj.onc.1204599 | department = review }}</ref><ref>{{Cite journal|last=Arndt|first=C. A.|last2=Crist|first2=W. M.|date=1999-07-29|title=Common musculoskeletal tumors of childhood and adolescence|journal=The New England Journal of Medicine|volume=341|issue=5|pages=342–352|doi=10.1056/NEJM199907293410507|issn=0028-4793|pmid=10423470|pmc=3538469}}</ref> This 2;13 translocation breaks and rejoins portions of the PAX3 and [[FOXO1]] genes to generate a PAX3-FOXO1 fusion gene that expresses a PAX3-FOXO1 fusion transcript encoding a PAX3-FOXO1 fusion protein.<ref>{{cite journal | vauthors = Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, Rauscher FJ, Emanuel BS, Rovera G, Barr FG | title = Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma | journal = Nature Genetics | volume = 5 | issue = 3 | pages = 230–5 | date = November 1993 | pmid = 8275086 | doi = 10.1038/ng1193-230 | department = primary }}</ref> PAX3 and FOXO1 encode transcription factors, and the translocation results in a fusion transcription factor containing the N-terminal PAX3 DNA-binding domain and the C-terminal FOXO1 transactivation domain. A smaller subset of ARMS cases is associated with less common fusions of PAX7 to FOXO1 or rare fusions of PAX3 to other transcription factors, such as NCOA1.<ref>{{cite journal | vauthors = Shern JF, Chen L, Chmielecki J, Wei JS, Patidar R, Rosenberg M, Ambrogio L, Auclair D, Wang J, Song YK, Tolman C, Hurd L, Liao H, Zhang S, Bogen D, Brohl AS, Sindiri S, Catchpoole D, Badgett T, Getz G, Mora J, Anderson JR, Skapek SX, Barr FG, Meyerson M, Hawkins DS, Khan J | display-authors = 6 | title = Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors | journal = Cancer Discovery | volume = 4 | issue = 2 | pages = 216–31 | date = February 2014 | pmid = 24436047 | doi = 10.1158/2159-8290.CD-13-0639 | department = primary | pmc = 4462130 }}</ref><ref>{{Cite journal|last=Barr|first=Frederic G.|date=1995-02-15|title=Molecular Assays for Chromosomal Translocations in the Diagnosis of Pediatric Soft Tissue Sarcomas|url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.1995.03520310051029|journal=JAMA: The Journal of the American Medical Association|language=en|volume=273|issue=7|doi=10.1001/jama.1995.03520310051029|issn=0098-7484}}</ref> Compared to the wild-type PAX3 protein, the PAX3-FOXO1 fusion protein more potently activates PAX3 target genes.<ref name="Bennicelli_1996" /> In ARMS cells, PAX3-FOXO1 usually functions as a transcriptional activator and excessively increases expression of downstream target genes.<ref>{{cite journal | vauthors = Davicioni E, Finckenstein FG, Shahbazian V, Buckley JD, Triche TJ, Anderson MJ | title = Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas | journal = Cancer Research | volume = 66 | issue = 14 | pages = 6936–46 | date = July 2006 | pmid = 16849537 | doi = 10.1158/0008-5472.CAN-05-4578 | department = primary }}</ref><ref>{{cite journal | vauthors = Cao L, Yu Y, Bilke S, Walker RL, Mayeenuddin LH, Azorsa DO, Yang F, Pineda M, Helman LJ, Meltzer PS | title = Genome-wide identification of PAX3-FKHR binding sites in rhabdomyosarcoma reveals candidate target genes important for development and cancer | journal = Cancer Research | volume = 70 | issue = 16 | pages = 6497–508 | date = August 2010 | pmid = 20663909 | doi = 10.1158/0008-5472.CAN-10-0582 | department = primary | pmc = 2922412 }}</ref> In addition, PAX3-FOXO1 binds along with MYOD1, MYOG and MYCN as well as chromatin structural proteins, such as CHD4 and BRD4, to contribute to the formation of super enhancers in the vicinity of a subset of these target genes.<ref>{{cite journal | vauthors = Gryder BE, Yohe ME, Chou HC, Zhang X, Marques J, Wachtel M, Schaefer B, Sen N, Song Y, Gualtieri A, Pomella S, Rota R, Cleveland A, Wen X, Sindiri S, Wei JS, Barr FG, Das S, Andresson T, Guha R, Lal-Nag M, Ferrer M, Shern JF, Zhao K, Thomas CJ, Khan J | display-authors = 6 | title = PAX3-FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability | journal = Cancer Discovery | volume = 7 | issue = 8 | pages = 884–899 | date = August 2017 | pmid = 28446439 | doi = 10.1158/2159-8290.CD-16-1297 | department = primary }}</ref> These dysregulated target genes contribute to tumorigenesis by altering signaling pathways that affect proliferation, cell death, myogenic differentiation, and migration.
 
A t(2;4)(q35;q31.1) chromosomal translocation that fuses the PAX3 and MAML3 genes occurs in [[biphenotypic sinonasal sarcoma]] (BSNS), a low-grade adult malignancy associated with both myogenic and neural differentiation.<ref>{{cite journal | vauthors = Wang X, Bledsoe KL, Graham RP, Asmann YW, Viswanatha DS, Lewis JE, Lewis JT, Chou MM, Yaszemski MJ, Jen J, Westendorf JJ, Oliveira AM | title = Recurrent PAX3-MAML3 fusion in biphenotypic sinonasal sarcoma | journal = Nature Genetics | volume = 46 | issue = 7 | pages = 666–8 | date = July 2014 | pmid = 24859338 | pmc = 4236026 | doi = 10.1038/ng.2989 | department = primary }}</ref> MAML3 encodes a transcriptional coactivator involved in Notch signaling. The PAX3-MAML3 fusion juxtaposes the N-terminal PAX3 DNA binding domain with the C-terminal MAML3 transactivation domain to create another potent activator of target genes with PAX3 binding sites. Of note, PAX3 is rearranged without MAML3 involvement in a smaller subset of BSNS cases, and some of these variant cases contain a PAX3-NCOA1 or PAX3-FOXO1 fusion.<ref>{{cite journal | vauthors = Fritchie KJ, Jin L, Wang X, Graham RP, Torbenson MS, Lewis JE, Rivera M, Garcia JJ, Schembri-Wismayer DJ, Westendorf JJ, Chou MM, Dong J, Oliveira AM | display-authors = 6 | title = Fusion gene profile of biphenotypic sinonasal sarcoma: an analysis of 44 cases | journal = Histopathology | volume = 69 | issue = 6 | pages = 930–936 | date = December 2016 | pmid = 27454570 | doi = 10.1111/his.13045 | department = primary }}</ref><ref>{{cite journal | vauthors = Huang SC, Ghossein RA, Bishop JA, Zhang L, Chen TC, Huang HY, Antonescu CR | title = Novel PAX3-NCOA1 Fusions in Biphenotypic Sinonasal Sarcoma With Focal Rhabdomyoblastic Differentiation | journal = The American Journal of Surgical Pathology | volume = 40 | issue = 1 | pages = 51–9 | date = January 2016 | pmid = 26371783 | pmc = 4679641 | doi = 10.1097/PAS.0000000000000492 }}</ref> Though PAX3-FOXO1 and PAX3-NCOA1 fusions can be formed in both ARMS and BSNS, there are differences in the pattern of activated downstream target genes suggesting that the cell environment has an important role in modulating the output of these fusion transcription factors.
 
In addition to tumors with PAX3-related fusion genes, there are several other tumor categories that express the wild-type PAX3 gene. The presence of PAX3 expression in some tumors can be explained by their derivation from developmental lineages normally expressing wild-type PAX3. For example, PAX3 is expressed in cancers associated with neural tube-derived lineages, (e.g., glioblastoma), neural crest-derived lineages (e.g., melanoma) and myogenic lineages (e.g., embryonal rhabdomyosarcoma).<ref name="Xia_2014">{{cite journal | vauthors = Xia L, Huang Q, Nie D, Shi J, Gong M, Wu B, Gong P, Zhao L, Zuo H, Ju S, Chen J, Shi W | title = PAX3 is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells | journal = Brain Research | volume = 1521 | pages = 68–78 | date = July 2013 | pmid = 23701726 | doi = 10.1016/j.brainres.2013.05.021 | department = primary }}</ref><ref name="Scholl_2001">{{cite journal | vauthors = Scholl FA, Kamarashev J, Murmann OV, Geertsen R, Dummer R, Schäfer BW | title = PAX3 is expressed in human melanomas and contributes to tumor cell survival | journal = Cancer Research | volume = 61 | issue = 3 | pages = 823–6 | date = February 2001 | pmid = 11221862 | department = primary }}</ref><ref>{{cite journal | vauthors = Barr FG, Fitzgerald JC, Ginsberg JP, Vanella ML, Davis RJ, Bennicelli JL | title = Predominant expression of alternative PAX3 and PAX7 forms in myogenic and neural tumor cell lines | journal = Cancer Research | volume = 59 | issue = 21 | pages = 5443–8 | date = November 1999 | pmid = 10554014 | department = primary }}</ref><ref>{{cite journal | vauthors = Plummer RS, Shea CR, Nelson M, Powell SK, Freeman DM, Dan CP, Lang D | title = PAX3 expression in primary melanomas and nevi | journal = Modern Pathology | volume = 21 | issue = 5 | pages = 525–30 | date = May 2008 | pmid = 18327212 | pmc = 2987639 | doi = 10.1038/modpathol.3801019 }}</ref> However, PAX3 is also expressed in other cancer types without a clear relationship to a PAX3-expressing developmental lineages, such as breast carcinoma and osteosarcoma.<ref>{{cite journal | vauthors = Jones AM, Mitter R, Poulsom R, Gillett C, Hanby AM, Tomlinson IP, Sawyer EJ | title = mRNA expression profiling of phyllodes tumours of the breast: identification of genes important in the development of borderline and malignant phyllodes tumours | journal = The Journal of Pathology | volume = 216 | issue = 4 | pages = 408–17 | date = December 2008 | pmid = 18937276 | doi = 10.1002/path.2439 | department = primary }}</ref><ref>{{cite journal | vauthors = Liu Q, Yang G, Qian Y | title = Loss of MicroRNA-489-3p promotes osteosarcoma metastasis by activating PAX3-MET pathway | journal = Molecular Carcinogenesis | volume = 56 | issue = 4 | pages = 1312–1321 | date = April 2017 | pmid = 27859625 | doi = 10.1002/mc.22593 | department = primary }}</ref> In these wild-type PAX3-expressing cancers, PAX3 function impacts on the control of proliferation, apoptosis, differentiation and motility.<ref name="Xia_2014" /><ref name="Scholl_2001" /> Therefore wild-type PAX3 exerts a regulatory role in tumorigenesis and tumor progression, which may be related to its role in normal development.
 
== References ==
{{reflist|32em}}
 
== Further reading ==
{{refbegin|32em}}
* {{cite journal | vauthors = Wachtel M, Schäfer BW | title = PAX3-FOXO1: Zooming in on an "undruggable" target | journal = Seminars in Cancer Biology | volume = | issue = | pages = | year = 2017 | pmid = 29146205 | doi = 10.1016/j.semcancer.2017.11.006 | department = review }}
* {{cite journal | vauthors = Kubo T, Shimose S, Fujimori J, Furuta T, Ochi M | title = Prognostic value of PAX3/7-FOXO1 fusion status in alveolar rhabdomyosarcoma: Systematic review and meta-analysis | journal = Critical Reviews in Oncology/hematology | volume = 96 | issue = 1 | pages = 46–53 | year = 2015 | pmid = 26008753 | doi = 10.1016/j.critrevonc.2015.04.012 | department = review }}
* {{cite journal | vauthors = Buckingham M, Relaix F | title = PAX3 and PAX7 as upstream regulators of myogenesis | journal = Seminars in Cell & Developmental Biology | volume = 44 | issue = | pages = 115–25 | year = 2015 | pmid = 26424495 | doi = 10.1016/j.semcdb.2015.09.017 | department = review }}
* {{cite journal | vauthors = Eccles MR, He S, Ahn A, Slobbe LJ, Jeffs AR, Yoon HS, Baguley BC | title = MITF and PAX3 Play Distinct Roles in Melanoma Cell Migration; Outline of a "Genetic Switch" Theory Involving MITF and PAX3 in Proliferative and Invasive Phenotypes of Melanoma | journal = Frontiers in Oncology | volume = 3 | issue = | pages = 229 | year = 2013 | pmid = 24062982 | pmc = 3769631 | doi = 10.3389/fonc.2013.00229 | department = review }}
* {{cite journal | vauthors = Olanich ME, Barr FG | title = A call to ARMS: targeting the PAX3-FOXO1 gene in alveolar rhabdomyosarcoma | journal = Expert Opinion on Therapeutic Targets | volume = 17 | issue = 5 | pages = 607–23 | year = 2013 | pmid = 23432728 | doi = 10.1517/14728222.2013.772136 | department = review }}
* {{cite journal | vauthors = Medic S, Ziman M | title = PAX3 across the spectrum: from melanoblast to melanoma | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 44 | issue = 2-3 | pages = 85–97 | year = 2009 | pmid = 19401874 | doi = 10.1080/10409230902755056 | department = review }}
* {{cite journal | vauthors = Kubic JD, Young KP, Plummer RS, Ludvik AE, Lang D | title = Pigmentation PAX-ways: the role of Pax3 in melanogenesis, melanocyte stem cell maintenance, and disease | journal = Pigment Cell & Melanoma Research | volume = 21 | issue = 6 | pages = 627–45 | year = 2008 | pmid = 18983540 | pmc = 2979299 | doi = 10.1111/j.1755-148X.2008.00514.x | department = review }}
{{refend}}
{{refend}}


== External links ==
== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1531/  GeneReviews/NCBI/NIH/UW entry on Waardenburg Syndrome Type I]
* {{MeshName|PAX3+protein,+human}}
* {{MeshName|PAX3+protein,+human}}


Latest revision as of 13:08, 4 November 2018

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The PAX3 (paired box gene 3) gene encodes a member of the paired box or PAX family of transcription factors.[1] The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in a subfamily along with the highly homologous human PAX7 and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 exons within a 100 kb region.

Transcript splicing

Alternative splicing and processing generates multiple PAX3 isoforms that have been detected at the mRNA level.[2] PAX3e is the longest isoform and consists of 10 exons that encode a 505 amino acid protein. In other mammalian species, including mouse, the longest mRNAs correspond to the human PAX3c and PAX3d isoforms, which consist of the first 8 or 9 exons of the PAX3 gene, respectively. Shorter PAX3 isoforms include mRNAs that skip exon 8 (PAX3g and PAX3h) and mRNAs containing 4 or 5 exons (PAX3a and PAX3b). In limited studies comparing isoform expression, PAX3d is expressed at the highest levels. From a functional standpoint, PAX3c, PAX3d, and PAX3h stimulate activities such as cell growth whereas PAX3e and PAX3g inhibit these activities, and PAX3a and PAX3b show no activity or inhibit these endpoints.

A common alternative splice affecting the PAX3 mRNA involves the sequence CAG at the 5’ end of exon 3.[3] This splice either includes or excludes these three bases, thus resulting in the presence or absence of a glutamine residue in the paired box motif. Limited sequencing studies of full-length human cDNAs identified this splicing event as a variant of the PAX3d isoform, and this spliced isoform has been separately termed the PAX3i isoform. The Q+ and Q- isoforms of PAX3 are generally co-expressed in cells. At the functional level, the Q+ isoform shows similar or less DNA binding and transcriptional activation than the Q- isoform.

Protein structure and function

File:PAX3.hg38.fig.new.7.tif
Structure of the PAX3 gene, mRNA and protein. The exons in the DNA and mRNA diagrams are numbered, and a horizontal arrow in the DNA diagram shows the promoter and direction of transcription. The start and stop codons are shown in the mRNA diagram by the vertical arrows. Conserved regions are indicated by open boxes in the protein diagram, and functional domains are indicated as thick horizontal lines above the protein diagram. Representative sizes are shown by the thin horizontal line segments in the DNA, mRNA and protein diagrams. Abbreviations: PB, paired box domain; HD, homeodomain; PST, proline-, serine- and threonine-rich region; DBD, DNA binding domain; TAD, transcription activation domain.

PAX3 encodes a transcription factor with an N-terminal DNA binding domain consisting of a paired box (PD) encoded by exons 2, 3, and 4, and an octapeptide and complete homeodomain (HD) encoded by exons 5 and 6.[4] In addition, the PAX3 protein has a C-terminal transcriptional activation domain encoded by exons 7 and 8. The highly conserved PD consists of a 128 amino acid region that binds to DNA sequences related to the TCACGC/G motif.[5] The HD motif usually consists of 60 amino acids and binds to sequences containing a TAAT core motif.[6] The combination of these two DNA binding domains enable the PAX3 protein to recognize longer sequences containing PD and HD binding sites.[7] In the C-terminus of PAX3, there is a proline, serine and threonine (PST)-rich region measuring 78 amino acids that functions to stimulate transcriptional activity.[8] There are also transcriptional repression domains in the HD and N-terminal region (including the first half of the PD) that repress the C-terminal transcriptional activation domain.[9]

PAX3 functions as a transcriptional activator for most target genes, but also may repress a smaller subset of target genes.[10] These expression changes are effected through binding of PAX3 to specific recognition sites, which are situated in various genomic locations.[11] Some binding sites are located in or near target genes, such as the 5’ promoter, first intron and 3’ untranslated region. A substantial number of PAX3 binding sites are located at larger distances upstream and downstream of target genes. Among the PAX3 target genes, there is one group associated with muscle development and a second group associated with neural and melanocyte development. The proteins encoded by these target genes regulate various functional activities in these lineages, including differentiation, proliferation, migration, adhesion, and apoptosis.

PAX3 interacts with other nuclear proteins, which modulate PAX3 transcriptional activity. Dimerization of PAX3 with another PAX3 molecule or a PAX7 molecule enables binding to a palindromic HD binding site (TAATCAATTA).[12] Interaction of PAX3 with other transcription factors (such as SOX10) or chromatin factors (such as PAX3/7BP) enables synergistic activation of PAX3 target genes.[13][14] In contrast, binding of PAX3 to co-repressors, such as calmyrin, inhibits activation of PAX3 target genes.[15] These co-repressors may function by altering chromatin structure at target genes, inhibiting PAX3 recognition of its DNA binding site or directly altering PAX3 transcriptional activity.

Finally, PAX3 protein expression and function can be modulated by post-translational modifications. PAX3 can be phosphorylated at serines 201, 205 and 209 by kinases such as GSK3b, which in some settings will increase PAX3 protein stability.[16][17] In addition, PAX3 can also undergo ubiquitination and acetylation at lysines 437 and 475, which regulates protein stability and function.[18][19]

Table 1. Representative PAX3 transcriptional target genes.

Protein category Name Phenotypic Activity
Cell adhesion molecule NRCAM Intercellular adhesion
Chemokine receptor CXCR4 Motility
Receptor tyrosine kinase FGFR4 Proliferation, differentiation, migration
MET Proliferation, migration, survival
RET Proliferation, migration, differentiation
Transcription factor MITF Differentiation, proliferation, survival
MYF5 Differentiation
MYOD1 Differentiation

Expression during development

During development, one of the major lineages expressing Pax3 is the skeletal muscle lineage.[20] Pax3 expression is first seen in the pre-somitic paraxial mesoderm, and then ultimately becomes restricted to the dermomyotome, which forms from the dorsal region of the somites. To form skeletal muscle in central body segments, PAX3-expressing cells detach from the dermomyotome and then Pax3 expression is turned off as Myf5 and MyoD1 expression is activated. To form other skeletal muscles, Pax3-expressing cells detach from the dermomyotome and migrate to more distant sites, such as the limbs and diaphragm. A subset of these Pax3-expressing dermomyotome-derived cells also serves as an ongoing progenitor pool for skeletal muscle growth during fetal development. During later developmental stages, myogenic precursors expressing Pax3 and/or Pax7 form satellite cells within the skeletal muscle, which contribute to postnatal muscle growth and muscle regeneration. These adult satellite cells remain quiescent until injury occurs, and then are stimulated to divide and regenerate the injured muscle.

Pax3 is also involved in the development of the nervous system.[21] Expression of Pax3 is first detected in the dorsal region of the neural groove and, as this neural groove deepens to form the neural tube, Pax3 is expressed in the dorsal portion of the neural tube. As the neural tube enlarges, Pax3 expression is localized to proliferative cells in the inner ventricular zone and then this expression is turned off as these cells migrate to more superficial regions. Pax3 is expressed along the length of the neural tube and throughout much of the developing brain, and this expression is subsequently turned off during later developmental stages in a rostral to caudal direction.

During early development, Pax3 expression also occurs at the lateral and posterior margins of the neural plate, which is the region from which the neural crest arises.[22] Pax3 is later expressed by various cell types and structures arising from the neural crest, such as melanoblasts, Schwann cell precursors, and dorsal root ganglia. In addition, Pax3-expressing cells derived from the neural crest contribute to the formation of other structures, such as the inner ear, mandible and maxilla.[23]

Germline mutations in disease

Germline mutations of the Pax3 gene cause the splotch phenotype in mice.[24][25] At the molecular level, this phenotype is caused by point mutations or deletions that alter or abolish Pax3 transcriptional function. In the heterozygous state, the splotch phenotype is characterized by white patches in the belly, tail and feet. These white spots are attributed to localized deficiencies in pigment-forming melanocytes resulting from neural crest cell defects. In the homozygous state, these Pax3 mutations cause embryonic lethality, which is associated with prominent neural tube closure defects and abnormalities of neural crest-derived structures, such as melanocytes, dorsal root ganglia and enteric ganglia. Heart malformations also result from the loss of cardiac neural crest cells, which normally contribute to the cardiac outflow tract and innervation of the heart. Finally, limb musculature does not develop in the homozygotes and axial musculature demonstrates varying abnormalities. These myogenic effects are caused by increased cell death of myogenic precursors in the dermomyotome and diminished migration from the dermomyotome.

Germline mutations of the PAX3 gene occur in the human disease Waardenburg syndrome,[26] which consists of four autosomal dominant genetic disorders (WS1, WS2, WS3 and WS4).[27] Of the four subtypes, WS1 and WS3 are usually caused by PAX3 mutations. All four subtypes are characterized by hearing loss, eye abnormalities and pigmentation disorders. In addition, WS1 is frequently associated with a midfacial alteration called dystopia canthorum, while WS3 (Klein-Waardenburg syndrome) is frequently distinguished by musculoskeletal abnormalities affecting the upper limbs. Most WS1 cases are caused by heterozygous PAX3 mutations while WS3 is caused by either partial or total deletion of PAX3 and contiguous genes or by smaller PAX3 mutations in the heterozygous or homozygous state. These PAX3 mutations in WS1 and WS3 include missense, nonsense and splicing mutations; small insertions; and small or gross deletions. Though these changes are usually not recurrent, the mutations generally occur in exons 2 through 6 with exon 2 mutations being most common. As these exons encode the paired box and homeodomain, these mutations often affect DNA binding function.

Mutations in human cancer

Alveolar rhabdomyosarcoma (ARMS) is an aggressive soft tissue sarcoma that occurs in children and is usually characterized by a recurrent t(2;13)(q35;q14) chromosomal translocation.[28][29] This 2;13 translocation breaks and rejoins portions of the PAX3 and FOXO1 genes to generate a PAX3-FOXO1 fusion gene that expresses a PAX3-FOXO1 fusion transcript encoding a PAX3-FOXO1 fusion protein.[30] PAX3 and FOXO1 encode transcription factors, and the translocation results in a fusion transcription factor containing the N-terminal PAX3 DNA-binding domain and the C-terminal FOXO1 transactivation domain. A smaller subset of ARMS cases is associated with less common fusions of PAX7 to FOXO1 or rare fusions of PAX3 to other transcription factors, such as NCOA1.[31][32] Compared to the wild-type PAX3 protein, the PAX3-FOXO1 fusion protein more potently activates PAX3 target genes.[9] In ARMS cells, PAX3-FOXO1 usually functions as a transcriptional activator and excessively increases expression of downstream target genes.[33][34] In addition, PAX3-FOXO1 binds along with MYOD1, MYOG and MYCN as well as chromatin structural proteins, such as CHD4 and BRD4, to contribute to the formation of super enhancers in the vicinity of a subset of these target genes.[35] These dysregulated target genes contribute to tumorigenesis by altering signaling pathways that affect proliferation, cell death, myogenic differentiation, and migration.

A t(2;4)(q35;q31.1) chromosomal translocation that fuses the PAX3 and MAML3 genes occurs in biphenotypic sinonasal sarcoma (BSNS), a low-grade adult malignancy associated with both myogenic and neural differentiation.[36] MAML3 encodes a transcriptional coactivator involved in Notch signaling. The PAX3-MAML3 fusion juxtaposes the N-terminal PAX3 DNA binding domain with the C-terminal MAML3 transactivation domain to create another potent activator of target genes with PAX3 binding sites. Of note, PAX3 is rearranged without MAML3 involvement in a smaller subset of BSNS cases, and some of these variant cases contain a PAX3-NCOA1 or PAX3-FOXO1 fusion.[37][38] Though PAX3-FOXO1 and PAX3-NCOA1 fusions can be formed in both ARMS and BSNS, there are differences in the pattern of activated downstream target genes suggesting that the cell environment has an important role in modulating the output of these fusion transcription factors.

In addition to tumors with PAX3-related fusion genes, there are several other tumor categories that express the wild-type PAX3 gene. The presence of PAX3 expression in some tumors can be explained by their derivation from developmental lineages normally expressing wild-type PAX3. For example, PAX3 is expressed in cancers associated with neural tube-derived lineages, (e.g., glioblastoma), neural crest-derived lineages (e.g., melanoma) and myogenic lineages (e.g., embryonal rhabdomyosarcoma).[39][40][41][42] However, PAX3 is also expressed in other cancer types without a clear relationship to a PAX3-expressing developmental lineages, such as breast carcinoma and osteosarcoma.[43][44] In these wild-type PAX3-expressing cancers, PAX3 function impacts on the control of proliferation, apoptosis, differentiation and motility.[39][40] Therefore wild-type PAX3 exerts a regulatory role in tumorigenesis and tumor progression, which may be related to its role in normal development.

References

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Further reading

External links

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