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PDGF signaling specificity is mediated through multiple immediate early genes

Nature Genetics volume 39, pages 52–60 (2007)Cite this article

Abstract

Growth factor signaling leads to the induction or repression of immediate early genes, but how these genes act collectively as effectors of downstream processes remains unresolved. We have used gene trap–coupled microarray analysis to identify and mutate multiple platelet-derived growth factor (PDGF) intermediate early genes in mice. Mutations in these genes lead to a high frequency of phenotypes that affect the same cell types and processes as those controlled by the PDGF pathway. We conclude that these genes form a network that controls specific processes downstream of PDGF signaling.

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Figure 1: Mutations in some PDGF targets alter growth rates in mice.
Figure 2: PDGF target genes are necessary for normal vascular development.
Figure 3: PDGF target genes are necessary for kidney glomerular development and function.
Figure 4: PDGF target genes are necessary for normal skeletal morphology of the palate, ribs and vertebrae.
Figure 5: Mutations in PDGF targets affect cell movement.
Figure 6: The skeletal phenotypes of PDGF target genes are additive with the dosage of Pdgfra and with each other.
Figure 7: Craniofacial abnormalities in PDGF target gene mutations are enhanced by Pdgfra heterozygosity.

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Acknowledgements

We thank P. Corrin and M. Grenley for excellent technical assistance; B. Hoplight for assistance with statistical analysis and our laboratory colleagues S. Parkhurst and M. Van Gilst for critical reading of the manuscript. The Sox10 probe was a gift of M. Wegner (Universität Erlangen). J.S. and C.S.R. were the recipients of postdoctoral fellowships from the US National Institute of General Medical Sciences (GM071158) and from the Leukemia and Lymphoma Society, respectively, and both were supported by a Chromosome and Metabolism Training Grant (CA09657). This work was supported by grant HD24875 from the National Institute of Child Health and Human Development to P.S.

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Authors and Affiliations

  1. Program in Developmental Biology and Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, 98109, Washington, USA

    Jennifer Schmahl, Christopher S Raymond & Philippe Soriano

Authors
  1. Jennifer Schmahl
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  2. Christopher S Raymond
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  3. Philippe Soriano
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Contributions

J.S. and P.S. conceived and designed the experiments, P.S. generated chimeras and determined viability of mutant strains, C.S.R. focused on Sgpl1−/− mice, J.S. performed characterization of all the strains and analyzed the data and J.S. and P.S. wrote the paper.

Corresponding author

Correspondence to Philippe Soriano.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Identification and verification of the insertion sites of the gene trap construct. (PDF 319 kb)

Supplementary Fig. 2

PDGF target genes are expressed in PDGF-dependent tissues. (PDF 305 kb)

Supplementary Fig. 3

Expression of PDGF target genes is altered in PDGFRβ−/− embryos. (PDF 223 kb)

Supplementary Table 1

Gene identification and insertion site. (PDF 92 kb)

Supplementary Table 2

Viability is reduced in mice with mutations in PDGF target genes. (PDF 95 kb)

Supplementary Table 3

Penetrance of skeletal defects in affected bones. (PDF 53 kb)

Supplementary Table 4

Primers used for genotyping mutant mice, for RT-PCR and for semiquantitative PCR. (PDF 60 kb)

Supplementary Note (PDF 95 kb)

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Schmahl, J., Raymond, C. & Soriano, P. PDGF signaling specificity is mediated through multiple immediate early genes. Nat Genet 39, 52–60 (2007). https://doi.org/10.1038/ng1922

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