Altered regulation of platelet-derived growth factor receptor-alpha gene-transcription in vitro by spina bifida-associated mutant Pax1 proteins

Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14459-63. doi: 10.1073/pnas.95.24.14459.


Mouse models show that congenital neural tube defects (NTDs) can occur as a result of mutations in the platelet-derived growth factor receptor-alpha gene (PDGFRalpha). Mice heterozygous for the PDGFRalpha-mutation Patch, and at the same time homozygous for the undulated mutation in the Pax1 gene, exhibit a high incidence of lumbar spina bifida occulta, suggesting a functional relation between PDGFRalpha and Pax1. Using the human PDGFRalpha promoter linked to a luciferase reporter, we show in the present paper that Pax1 acts as a transcriptional activator of the PDGFRalpha gene in differentiated Tera-2 human embryonal carcinoma cells. Two mutant Pax1 proteins carrying either the undulated-mutation or the Gln --> His mutation previously identified by us in the PAX1 gene of a patient with spina bifida, were not or less effective, respectively. Surprisingly, Pax1 mutant proteins appear to have opposing transcriptional activities in undifferentiated Tera-2 cells as well as in the U-2 OS osteosarcoma cell line. In these cells, the mutant Pax1 proteins enhance PDGFRalpha-promoter activity whereas the wild-type protein does not. The apparent up-regulation of PDGFRalpha expression in these cells clearly demonstrates a gain-of-function phenomenon associated with mutations in Pax genes. The altered transcriptional activation properties correlate with altered protein-DNA interaction in band-shift assays. Our data provide additional evidence that mutations in Pax1 can act as a risk factor for NTDs and suggest that the PDGFRalpha gene is a direct target of Pax1. In addition, the results support the hypothesis that deregulated PDGFRalpha expression may be causally related to NTDs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Base Sequence
  • Carcinoma, Embryonal
  • DNA Primers
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation*
  • Glutamine
  • Histidine
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Paired Box Transcription Factors
  • Point Mutation*
  • Promoter Regions, Genetic
  • Protein Biosynthesis
  • Receptor, Platelet-Derived Growth Factor alpha
  • Receptors, Platelet-Derived Growth Factor / biosynthesis
  • Receptors, Platelet-Derived Growth Factor / genetics*
  • Recombinant Fusion Proteins / biosynthesis
  • Spinal Dysraphism / genetics*
  • Trans-Activators / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Transfection
  • Tumor Cells, Cultured


  • DNA Primers
  • DNA-Binding Proteins
  • Paired Box Transcription Factors
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Transcription Factors
  • Glutamine
  • PAX1 transcription factor
  • Histidine
  • Receptor, Platelet-Derived Growth Factor alpha
  • Receptors, Platelet-Derived Growth Factor