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The expression and function of PAX3 in development and disease.

ABSTRACT: The PAX3 gene encodes a member of the PAX family of transcription factors that is characterized by a highly conserved paired box motif. The PAX3 protein is a transcription factor consisting of an N-terminal DNA binding domain (containing a paired box and homeodomain) and a C-terminal transcriptional activation domain. This protein is expressed during development of skeletal muscle, central nervous system and neural crest derivatives, and regulates expression of target genes that impact on proliferation, survival, differentiation and motility in these lineages. Germline mutations of the murine Pax3 and human PAX3 genes cause deficiencies in these developmental lineages and result in the Splotch phenotype and Waardenburg syndrome, respectively. Somatic genetic rearrangements that juxtapose the PAX3 DNA binding domain to the transcriptional activation domain of other transcription factors deregulate PAX3 function and contribute to the pathogenesis of the soft tissue cancers alveolar rhabdomyosarcoma and biphenotypic sinonasal sarcoma. The wild-type PAX3 protein is also expressed in other cancers related to developmental lineages that normally express this protein and exerts phenotypic effects related to its normal developmental role.

SUBMITTER: Boudjadi S

PROVIDER: S-EPMC6624083 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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The expression and function of PAX3 in development and disease.

Boudjadi Salah S Chatterjee Bishwanath B Sun Wenyue W Vemu Prasantha P Barr Frederic G FG

Gene 20180504

The PAX3 gene encodes a member of the PAX family of transcription factors that is characterized by a highly conserved paired box motif. The PAX3 protein is a transcription factor consisting of an N-terminal DNA binding domain (containing a paired box and homeodomain) and a C-terminal transcriptional activation domain. This protein is expressed during development of skeletal muscle, central nervous system and neural crest derivatives, and regulates expression of target genes that impact on prolif ...[more]

PMID: 29730428

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Project description:Pax3 is an essential paired- and homeodomain-containing transcription factor that is necessary for closure of the neural tube, and morphogenesis of the migratory neural crest and myoblast lineages. Homozygous loss-of-function mutation results in mid-gestational lethality with defects in myogenesis, neural tube closure and neural crest-derived lineages including melanocytes, Schwann cells and insufficient mesenchymal cells to septate the cardiac outflow tract. To address the function of Pax3 in later fetal stages and in specific adult tissues, we generated a floxed Pax3 allele (Pax3(flox)). An intermediate allele (Pax3(neo)) was produced via creation of the floxed allele, in which the TK-neo(R) cassette is present between exons 5 and 6. It was deduced to be a hypomorph, as Pax3 protein expression is reduced by 80% and homozygote hypomorphs die postnatally. To assess the consequences of reduced Pax3 levels on the various Pax3-expressing lineages and to determine the underlying cause of lethality, we examined Pax3 spatiotemporal expression and the resultant defects. Defective limb and tongue musculature were observed and lethality was due to an inability to suckle. However, the heart, diaphragm, trunk musculature, as well as the various neural crest-derived lineages and neural tube were all unaffected by reduced Pax3 levels. Significantly, elevated levels of the related Pax7 protein were present in unaffected neural tube and epaxial somatic component. The limb and tongue myogenic defects were found to be due to a significant increase in apoptosis within the somites that leads to a paucity of migratory hypaxial myoblasts. These effects were attributed to the hypomorphic effect of the Pax3(neo) allele, as removal of the TK-neo(R) cassette completely relieves the hypomorphic effect, as 100% of the Pax3(flox/flox) mice were normal. These data demonstrate a lineage-specific response to approximately 80% loss of Pax3 protein expression, with myogenesis of limb and tongue being most sensitive to reduced Pax3 levels. Thus, we have established that there are different minimum threshold requirements for Pax3 within different Pax3-expressing lineages.

Dataset Information

The expression and function of PAX3 in development and disease.

Publications

The expression and function of PAX3 in development and disease.

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