Disease relevance of Pax3

• To investigate the role of the translocation-associated gene Pax3:Fkhr in alveolar rhabdomyosarcomas, we generated a Cre-mediated conditional knock-in of Pax3:Fkhr into the mouse Pax3 locus [1].
• Pax3 down-regulation and shut-off of melanogenesis in melanoma B16/F10.9 by interleukin-6 receptor signaling [2].
• Disruption of the Pax-3 gene causes the Splotch phenotype in mice and Waardenburg syndrome in humans [3].
• The transcription start site and DNA sequence elements required for the induction of Pax3 expression in differentiating P19 embryonal carcinoma cells have been localized [4].
• Development of a lethal congenital heart defect in the splotch (Pax3) mutant mouse [5].
• We found that persistent expression of Pax3 in cranial neural crest cells resulted in cleft palate, ocular defects, malformation of the sphenoid bone, and perinatal lethality [6].

High impact information on Pax3

• The role of these genes in the patterning of limb muscles is unknown, although mutation of Pax3 or Met causes disruption of limb muscle development at an initial step, disturbing the epithelial-to-mesenchymal transition of the somitic epithelium [7].
• Pax3 haploinsufficiency results in the mouse splotch and human Waardenburg syndrome (WSI and WSIII) phenotypes [8].
• Remarkably, splotch/Myf-5 double homozygotes have a dramatic phenotype not seen in the individual mutants: body muscles are absent [9].
• Ectopic Pax-3 activates MyoD and Myf-5 expression in embryonic mesoderm and neural tissue [10].
• Redefining the genetic hierarchies controlling skeletal myogenesis: Pax-3 and Myf-5 act upstream of MyoD [9].

Chemical compound and disease context of Pax3

• BACKGROUND: This study examines interactions of a mutation in Pax3, embryonic sex, advanced maternal age, and arsenite exposure in the splotch (Sp) mouse model, with the aim of describing gene-environment interactions for neural tube defects and embryonic lethality [11].
• Splotch is an established model of folate-sensitive neural tube defects, and homozygous mutant embryos develop spina bifida and sometimes exencephaly [12].
• RESULTS: Maternal diabetes inhibited Pax-3 expression and increased neural tube defects, and alpha-tocopherol blocked these effects [13].
• In addition, induction of oxidative stress with antimycin A inhibited Pax-3 expression and increased neural tube defects [13].
• Reduction in the frequency of neural tube defects in splotch mice by retinoic acid [14].

Biological context of Pax3

• Haploinsufficiency of c-met rescues this phenotype, confirming the direct genetic link with Pax3 [15].
• To investigate the actions of these transcription factors, both Pax3 and PAX3-FKHR were introduced into NIH 3T3 cells, and the resultant gene expression changes were analyzed with a murine cDNA microarray containing 2,225 elements [16].
• Disruption of Pax3 expression by antisense oligonucleotides significantly impairs MyoD activation by signals from neural tube/notochord and surface ectoderm in cultured presomitic mesoderm (PSM), and is accompanied by a marked increase in programmed cell death [17].
• We show that most cells migrating into the wing field express the Msx1(nlacZ )transgene, together with Pax3 [18].
• Using Pax3 gene transcripts as a marker of limb muscle progenitor cells as they migrate from the somites, we have defined precisely the somitic origin and timing of cell migration from somites to limb buds in the mouse [18].

Anatomical context of Pax3

• Pax3 and Pax7 have distinct and overlapping functions in adult muscle progenitor cells [19].
• We show that Pax3, the paralogue of Pax7, is also present in both quiescent and activated satellite cells in many skeletal muscles [19].
• Downstream genes through which Pax3 regulates cardiac neural crest development are unknown [20].
• Somites that label for Msx1(nlacZ )transgene expression in the forelimb region partially overlap with those that contribute Pax3-expressing cells to the forelimb [18].
• At the limb bud level, Six1 and Six4 homeogenes control early steps of myogenic cell delamination and migration from the somite through the control of Pax3 gene expression [21].

Associations of Pax3 with chemical compounds

• Over-expression of the chondroitin sulphate proteoglycan versican is associated with defective neural crest migration in the Pax3 mutant mouse (splotch) [22].
• Expression of the met receptor tyrosine kinase in muscle progenitor cells in somites and limbs is absent in Splotch mice [23].
• NTD risk is reduced in various models by different maternal nutrient supplements, including folic acid ( Pax3, Cart1, Cd mutants), inositol ( ct ) and methionine ( Axd ) [24].
• Pax3 was modified by the creation of Factor Xa cleavage sites at discrete locations in the PD, the HD, and in the linker segment joining the PD and the HD (Xa172, Xa189, and Xa216) in individual Pax3 mutants [25].
• Site-specific modification of single cysteine Pax3 mutants reveals reciprocal regulation of DNA binding activity of the paired and homeo domain [26].

Physical interactions of Pax3

• The EF-hand calcium-binding protein calmyrin inhibits the transcriptional and DNA-binding activity of Pax3 [27].

Regulatory relationships of Pax3

• Pax3 protein and mRNA levels decline steadily after IL6RIL6 treatment, and overexpression of an ectopic Pax3 cDNA suppresses the Mitf promoter inhibition [2].
• Pax3 may serve to negatively regulate versican expression during normal development, thereby guiding neural crest cells into their pathways of migration [22].
• In that network, Pax3 gene is apparently activated through Dach/Eya/Six feedback loop to mediate MyoD-driven myogenesis [28].
• Pax3 repressed a 1.3 kb MBP promoter fragment in cotransfection assays, suggesting that it represses MBP transcription [29].
• Pax3 regulates morphogenetic cell behavior in vitro coincident with activation of a PCP/non-canonical Wnt-signaling cascade [30].

Other interactions of Pax3

• Manipulation of the dominant-negative forms of these factors in satellite cell cultures demonstrates that Pax3 cannot replace the antiapoptotic function of Pax7 [19].
• At Theiler stage 17 (day 10.5 post coitum) of development, strongly altered expression patterns of Pax3 and Myf5 were observed in dorsal somite regions indicating that the dorsal myotome and dermomyotome were not differentiating properly [31].
• Lbx1 and Pax3 are co-expressed in all migrating hypaxial muscle precursors, raising the possibility that Lbx1 regulates their migration [32].
• These results establish Msx2 as an effector of Pax3 in cardiac neural crest development [20].
• Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo [21].

Analytical, diagnostic and therapeutic context of Pax3

• In this paper we demonstrate, using RT-PCR and in situ hybridisation, that Pax3 expression can serve as a marker of cardiac neural crest cells in the mouse embryo [33].
• Confirmation that these Pax3-positive cells are indeed cardiac neural crest is provided by experiments in which hearts were deprived of a source of colonising neural crest, by organ culture in vitro, with consequent lack of up-regulation of Pax3 [33].
• In an attempt to develop a sensitive animal model for maternal diabetes-induced NTDs, the present study uses chemically induced diabetes in an inbred mouse model with or without the splotch (Sp) mutation, a putatively nonfunctional allele of Pax3 [34].
• To investigate the mechanism of these contrasting phenotypes, we replaced Pax3 by Pax7 by using gene targeting in the mouse [35].
• In the present study, four discrete DNA elements within the 1.6 kbp promoter fragment are shown by electrophoretic mobility shift assays (EMSA) to exhibit sequence specific interactions with proteins present in nuclear extracts from P19 EC cells induced to express Pax3 by treatment with retinoic acid (RA) [36].

References