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Article: Conditional deletion of platelet derived growth factor receptor alpha (Pdgfra) in urorectal mesenchyme causes mesenchyme apoptosis and urorectal developmental anomalies in mice

TitleConditional deletion of platelet derived growth factor receptor alpha (Pdgfra) in urorectal mesenchyme causes mesenchyme apoptosis and urorectal developmental anomalies in mice
Authors
KeywordsPlatelet-Derived Growth Factor
Receptors
Platelet-Derived Growth Factor
Factor PDGF
Issue Date2019
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/cdd
Citation
Cell Death and Differentiation, 2019, v. 26 n. 8, p. 1396-1410 How to Cite?
AbstractIn mammals, urorectal development starts at early embryonic stage, defective urorectal development results in anorectal malformations, which are common congenital developmental defects of the anus and the urethra in newborns. The etiology and embryology of the defects are still largely unknown. Platelet-derived growth factor receptor alpha (Pdgfra) is a cell surface receptor tyrosine kinase, upon binding to its ligands (Pdgfa-d), mediates intracellular signaling and regulates embryonic development. The expression of Pdgfra is tightly regulated in the developing urorectal mesenchyme, and its dysregulation is associated with urorectal defects in animals with urorectal defects. Knockout of Pdgfra induces early embryo lethality which precludes investigation of Pdgfra in urorectal development. To address the temporal requirement of Pdgfra in urorectal development, we conditionally deleted Pdgfra in Pdgfra-expressing tissues using a tamoxifen inducible Cre-loxP approach in mice, examined the urorectal development in Pdgfra conditional knockout (Pdgfra-cKO) embryos. We showed that conditional deletion of Pdgfra in Pdgfra-expressing tissues at E10-E11 caused cloaca septation defect, anteriorly displaced anus, defective urogenital folds development and abnormal urethra tubularization in both male and female mice. Furthermore, we showed that Pdgfra was required for the survival of urorectal mesenchyme, deletion of Pdgfra caused apoptosis in the peri-cloacal, the peri-urethra and the urorectal septum mesenchyme of Pdgfra-cKO mutants, associated with an induction of p53, Ndrg1 and activation of caspase-3 in Pdgfra-cKO embryos. In conclusion, Pdgfra is required for the development and survival of the urorectal mesenchyme in embryo, dysregulated Pdgfra signaling induced urorectal defects in mice resembling human congenital diseases of anorectal malformations and hypospadias. Perturbation of PDGFRA signaling may contribute to anorectal malformations and hypospadias in human.
Persistent Identifierhttp://hdl.handle.net/10722/273392
ISSN
2019 Impact Factor: 10.717
2015 SCImago Journal Rankings: 4.219

 

DC FieldValueLanguage
dc.contributor.authorQIAN, C-
dc.contributor.authorWu, Z-
dc.contributor.authorNg, RCL-
dc.contributor.authorGarcia-Barcelo, MM-
dc.contributor.authorYuan, ZW-
dc.contributor.authorWong, KKY-
dc.contributor.authorTam, PKH-
dc.contributor.authorLui, VCH-
dc.date.accessioned2019-08-06T09:28:04Z-
dc.date.available2019-08-06T09:28:04Z-
dc.date.issued2019-
dc.identifier.citationCell Death and Differentiation, 2019, v. 26 n. 8, p. 1396-1410-
dc.identifier.issn1350-9047-
dc.identifier.urihttp://hdl.handle.net/10722/273392-
dc.description.abstractIn mammals, urorectal development starts at early embryonic stage, defective urorectal development results in anorectal malformations, which are common congenital developmental defects of the anus and the urethra in newborns. The etiology and embryology of the defects are still largely unknown. Platelet-derived growth factor receptor alpha (Pdgfra) is a cell surface receptor tyrosine kinase, upon binding to its ligands (Pdgfa-d), mediates intracellular signaling and regulates embryonic development. The expression of Pdgfra is tightly regulated in the developing urorectal mesenchyme, and its dysregulation is associated with urorectal defects in animals with urorectal defects. Knockout of Pdgfra induces early embryo lethality which precludes investigation of Pdgfra in urorectal development. To address the temporal requirement of Pdgfra in urorectal development, we conditionally deleted Pdgfra in Pdgfra-expressing tissues using a tamoxifen inducible Cre-loxP approach in mice, examined the urorectal development in Pdgfra conditional knockout (Pdgfra-cKO) embryos. We showed that conditional deletion of Pdgfra in Pdgfra-expressing tissues at E10-E11 caused cloaca septation defect, anteriorly displaced anus, defective urogenital folds development and abnormal urethra tubularization in both male and female mice. Furthermore, we showed that Pdgfra was required for the survival of urorectal mesenchyme, deletion of Pdgfra caused apoptosis in the peri-cloacal, the peri-urethra and the urorectal septum mesenchyme of Pdgfra-cKO mutants, associated with an induction of p53, Ndrg1 and activation of caspase-3 in Pdgfra-cKO embryos. In conclusion, Pdgfra is required for the development and survival of the urorectal mesenchyme in embryo, dysregulated Pdgfra signaling induced urorectal defects in mice resembling human congenital diseases of anorectal malformations and hypospadias. Perturbation of PDGFRA signaling may contribute to anorectal malformations and hypospadias in human.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/cdd-
dc.relation.ispartofCell Death and Differentiation-
dc.rightsThis is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: https://doi.org/[insert DOI]-
dc.subjectPlatelet-Derived Growth Factor-
dc.subjectReceptors-
dc.subjectPlatelet-Derived Growth Factor-
dc.subjectFactor PDGF-
dc.titleConditional deletion of platelet derived growth factor receptor alpha (Pdgfra) in urorectal mesenchyme causes mesenchyme apoptosis and urorectal developmental anomalies in mice-
dc.typeArticle-
dc.identifier.emailWu, Z: hannawu@hku.hk-
dc.identifier.emailNg, RCL: royclng@hku.hk-
dc.identifier.emailGarcia-Barcelo, MM: mmgarcia@hku.hk-
dc.identifier.emailWong, KKY: kkywong@hku.hk-
dc.identifier.emailTam, PKH: paultam@hku.hk-
dc.identifier.emailLui, VCH: vchlui@hku.hk-
dc.identifier.authorityNg, RCL=rp02376-
dc.identifier.authorityGarcia-Barcelo, MM=rp00445-
dc.identifier.authorityWong, KKY=rp01392-
dc.identifier.authorityTam, PKH=rp00060-
dc.identifier.authorityLui, VCH=rp00363-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/s41418-018-0216-2-
dc.identifier.pmid30323271-
dc.identifier.scopuseid_2-s2.0-85054913157-
dc.identifier.hkuros299613-
dc.identifier.volume26-
dc.identifier.issue8-
dc.identifier.spage1396-
dc.identifier.epage1410-
dc.publisher.placeUnited Kingdom-

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