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FLASH GENE

Symbol

PAX3

contributors: npt/pgu/shn - updated : 05-07-2018

HGNC name	paired box 3
HGNC id	8617

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	ARMS alveolar rhabdomyosarcoma CDHS craniofacial-deafness-hand syndrome WS1 Waardenburg syndrome, type 1 WS3 Waardenburg syndrome type 3
Location	2q36.1      Physical location : 223.064.605 - 223.163.715
Synonym name	paired box gene 3 (Waardenburg syndrome 1)
	paired domain gene HuP2
Synonym symbol(s)	HUP2, MGC120381, MGC120382, MGC120383, MGC120384, MGC134778

DNA

TYPE	functioning gene
STRUCTURE	99.09 kb     10 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
text structure	PAX3 promoter was found to have higher transcriptional activity than that of PAX7

MAPPING

cloned

Y

linked

N

status

confirmed

Map	cen - D2S339 - D2S2197 - PAX3 - D2S313 - D2S2300 - qter
Text	see WS1

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_181457 (transcript variant PAX3) 8 - 2017 NP_852122 - 479 - - NM_000438 (transcript variant PAX3A) 4 splicing 1489 NP_000429 - 215 - 2004 14639621 NM_013942 (transcript variant PAX3B) 5 splicing 1080 NP_039230 - 206 - 2004 14639621 NM_181458 (transcript variant PAX3D) 9 splicing 3355 NP_852123 53 484 - 2004 14639621 NM_181459 (transcript variant PAX3E) 10 splicing 3184 NP_852124 55 505 - 2004 14639621 NM_181460 (transcript variant PAX3H) 9 splicing codon stop 2923 NP_852125 45 407 - 2004 14639621 NM_181461 (transcript variant PAX3G) 8 splicing codon stop 3108 NP_852126 44 403 - 2004 14639621 NM_001127366 (transcript variant PAX3I) 9 splicing 3352 NP_001120838 - 483 - 2003 14639621

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Nervous brain       highly Respiratory respiratory tract larynx     highly Skin/Tegument skin       highly Visual eye uvea choroid

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial barrier lining retinal pigment epithelium (RPE)

cells

System Cell Pubmed Species Stage Rna symbol Skin/Tegument melanocyte

cell lineage	resident muscle progenitor cells
cell lines
fluid/secretion

at STAGE

Text	expressed during early neurogenesis

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a paired DNA binding domain with an homeo domain
	comprising two structurally distinct N terminal (NTS) and C terminal subdomains
	a truncated helix-turn helix DNA binding domain
	an intermediary octapeptide motif

conjugated

Acetylated

mono polymer

heteromer , dimer

HOMOLOGY

interspecies	ortholog to Pax3, Rattus norvegicus
	ortholog to Pax3, Mus musculus
	ortholog to PAX3, Pan troglodytes
	ortholog to pax3a, Danio rerio

intraspecies

homolog to PAX7

Homologene

FAMILY

paired homeobox protein (non HOX) family

CATEGORY

DNA associated , transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus

basic FUNCTION	involved in neurogenesis, in skeletal muscle development and in melanogenesis through MITF transactivation and maybe other processes (see BARMS2, WS1, WS2, WS3)
	essential for skeletal myogenesis and the expression of transcription factors Mox1 and Six1 and its cofactor Eya2
	plays a role in regulating HES1 and NEUROG2 activity and thereby stem cell maintenance and neurogenesis
	initiates a melanogenic cascade at a nodal point in adult melanocyte stem cell differentiation
	playing critical roles during fetal development
	with PAX7, function to maintain expression of myogenic regulatory factors, and promote population expansion, but are also required for myogenic differentiation to proceed
	PAX3 regulates TGFbeta2 by directly binding to cis-regulatory elements on its promoter
	Pax3 acetylation results in decreased Hes1 and increased Neurog2 activity, thereby promoting sensory neuron differentiation
	FOXD3 and PAX3 act together to affect survival and maintenance of cardiac neural crest progenitors
	regulator of GFAP transcription, which could bind the promoter region of GFAP and down regulate the GFAP level during the serum-induced astrocyte differentiation of neural stem cells
	both PAX3 and PAX7 transcripts are required for commitment of cells to the myogenic lineage, with each transcript having a distinct role
	essential for dorsal neural tube, early neural crest and muscle cell lineage morphogenesis, but is not required for subsequent cardiac neural crest progeny morphogenesis involving their migration to the heart or septation of the outflow tract
	regulates complex differentiation networks in both melanoma cells and melanocytes to maintain cells as "stem" cell-like
	contribute to melanoma development and progression
	plays an essential role in early skeletal muscle development
	PAX7 and its homologue PAX3 are important players in neural crest and muscle development

CELLULAR PROCESS

nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

development , neurogenesis

PATHWAY

metabolism

signaling

sensory transduction/hearing

PAX3/DMRT2/MYF5 regulatory cascade operating in stem cells of the epaxial dermomyotome to initiate skeletal muscle formation

a component

forming a heterodimer with PAX7

INTERACTION

DNA	MITF promoter
	promoter region of several factors including cannabinoid receptor-1, BMP4, EPHA2 and EPHA4
	activates MYOD1 gene

RNA

small molecule

protein	TATA-box-binding and retinoblastoma proteins
	Daxx
	Mox1 and Mox2
	EF-hand calcium-binding protein calmyrin
	PDZ-binding motif TAZ
	TGFbeta2
	HDAC10
	TAF1 binds directly to PAX3 and overexpression of TAF1 increases the level of monoubiquitinated PAX3 and its degradation by the proteasome
	negatively regulates GFAP expression during astrocyte differentiation
	interdependent regulatory loops involving PAX3 and PAX7 in the dorsal mesencephalic vesicle modulate MEIS2 expression
	CSNK2A1 is the kinase responsible for phosphorylation PAX3 at Ser209, but also enables us to propose a mechanism describing the ordered and differential phosphorylation of PAX3 throughout early myogenesis
	TCOF1 acts as a modifier of PAX3 during enteric nervous system development and in the pathogenesis of colonic aganglionosis
	GPR39 phosphorylating CAMK2A, CAMK2B contributes to the distinct roles of PAX3 and PAX7 in myogenic progression

cell & other

REGULATION

inhibited by

EF-hand calcium-binding protein calmyrin

repressed by

death-domain associated protein, Daxx

Phosphorylated by	protein kinase GSK3B phosphorylating PAX3 at serine 201
	is phosphorylated by CSNK2A1 at Ser205 in proliferating myoblast

Other	regulated by a regulatory loop between GLI2, MEOX1, and PAX3 that is essential for specification of mesodermal cells into the muscle lineage
	SUMO-1 modified PML can derepress Pax3 transcriptional activity through sequestration of the Daxx repressor into the nuclear bodies
	regulated by ubiquitination and proteasomal degradation during adult muscle stem cell activation

ASSOCIATED DISORDERS

corresponding disease(s)

CDHS , WS1 , WS3 , ARMS

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral fusion translocation     to FOXO1/FKHR in alveolar rhabdomyosarcoma with t(2;13)(q35,q14), promoting malignant phenotypes such as proliferation, motility, and to suppress differentiation tumoral fusion translocation     t(2;2)(q35;p23), which generates a fusion protein composed of PAX3 and the nuclear receptor coactivator NCOA1, in alveolar rhabdomyosarcoma

Susceptibility

Variant & Polymorphism

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

heterozygous Pax3-FKHR knock-in mice show developmental abnormalities: intraventricular septum defects, tricuspid valve insufficiency, and diaphragm defects, which caused congestive heart failure leading to perinatal death