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PDGFR? regulates craniofacial development through homodimers and functional heterodimers with PDGFR?.

ABSTRACT: Craniofacial development is a complex morphogenetic process, disruptions in which result in highly prevalent human birth defects. While platelet-derived growth factor (PDGF) receptor ? (PDGFR?) has well-documented functions in this process, the role of PDGFR? in murine craniofacial development is not well established. We demonstrate that PDGFR? and PDGFR? are coexpressed in the craniofacial mesenchyme of mid-gestation mouse embryos and that ablation of Pdgfrb in the neural crest lineage results in increased nasal septum width, delayed palatal shelf development, and subepidermal blebbing. Furthermore, we show that the two receptors genetically interact in this lineage, as double-homozygous mutant embryos exhibit an overt facial clefting phenotype more severe than that observed in either single-mutant embryo. We reveal a physical interaction between PDGFR? and PDGFR? in the craniofacial mesenchyme and demonstrate that the receptors form functional heterodimers with distinct signaling properties. Our studies thus uncover a novel mode of signaling for the PDGF family during vertebrate development.

SUBMITTER: Fantauzzo KA

PROVIDER: S-EPMC5131783 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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PDGFRβ regulates craniofacial development through homodimers and functional heterodimers with PDGFRα.

Fantauzzo Katherine A KA Soriano Philippe P

Genes & development 20161117 21

Craniofacial development is a complex morphogenetic process, disruptions in which result in highly prevalent human birth defects. While platelet-derived growth factor (PDGF) receptor α (PDGFRα) has well-documented functions in this process, the role of PDGFRβ in murine craniofacial development is not well established. We demonstrate that PDGFRα and PDGFRβ are coexpressed in the craniofacial mesenchyme of mid-gestation mouse embryos and that ablation of Pdgfrb in the neural crest lineage results ...[more]

PMID: 27856617

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Project description:Much of the bone, cartilage and smooth muscle of the vertebrate face is derived from neural crest (NC) cells. During craniofacial development, the anterior neural ridge (ANR) and olfactory pit (OP) signaling centers are responsible for driving the outgrowth, survival, and differentiation of NC populated facial prominences, primarily via FGF. While much is known about the functional importance of signaling centers, relatively little is understood of how these signaling centers are made and maintained. In this report we describe a dramatic craniofacial malformation in mice mutant for the zinc finger transcription factor gene Sp8. At E14.5 they show facial prominences that are reduced in size and underdeveloped, giving an almost faceless phenotype. At later times they show severe midline defects, excencephaly, hyperterlorism, cleft palate, and a striking loss of many NC and paraxial mesoderm derived cranial bones. Sp8 expression was primarily restricted to the ANR and OP regions during craniofacial development. Analysis of an extensive series of conditional Sp8 mutants confirmed the critical role of Sp8 in signaling centers, and not directly in the NC and paraxial mesoderm cells. The NC cells of the Sp8 mutants showed increased levels of apoptosis and decreased cell proliferation, thereby explaining the reduced sizes of the facial prominences. Perturbed gene expression in the Sp8 mutants was examined by laser capture microdissection coupled with microarrays, as well as in situ hybridization and immunostaining. The most dramatic differences included striking reductions in Fgf8 and Fgf17 expression in the ANR and OP signaling centers. We were also able to achieve genetic and pharmaceutical partial rescue of the Sp8 mutant phenotype by reducing Sonic Hedgehog (SHH) signaling. These results show that Sp8 primarily functions to promote Fgf expression in the ANR and OP signaling centers that drive the survival, proliferation, and differentiation of the NC and paraxial mesoderm that make the face.

Dataset Information

PDGFR? regulates craniofacial development through homodimers and functional heterodimers with PDGFR?.

Publications

PDGFRβ regulates craniofacial development through homodimers and functional heterodimers with PDGFRα.

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