COUP-TFI (chicken ovalbumin upstream promoter-transcription factor I) regulates cell migration and axogenesis in differentiating P19 embryonal carcinoma cells

Mol Endocrinol. 2000 Dec;14(12):1918-33. doi: 10.1210/mend.14.12.0562.


The developmental expression patterns of the nuclear orphan receptors COUP-TFs (chicken ovalbumin upstream promoter-transcription factors) have been correlated to neurogenesis in several animal species. Nevertheless, the role of COUP-TFs in neurogenesis remains unknown. We have studied the functional involvement of COUP-TFI in retinoic acid (RA)-induced neuronal differentiation of P19 embryonal carcinoma cells through two complementary approaches: 1) deregulated expression of COUP-TFI, and 2) inactivation of endogenous COUP-TFs by means of a dominant-negative COUP-TFI mutant. Low levels of wild-type (wt)COUP-TFI transgene expression did not inhibit neural cell fate and primarily enhanced neuron outgrowth from RA-treated P19 aggregates. In contrast, high COUP-TFI expression impeded the neuronal differentiation of P19 cells induced with RA, resulting in cell cultures lacking neurons. This morphological effect was correlated to an elevated level of E-cadherin mRNA. The dominant-negative COUP-TFI mutant induced cell packing after RA treatment and inhibited neurite extension and neuron outgrowth from aggregates. A RGD peptide interference assay indicated that endogenous COUP-TFs could favor migration of neurons through an integrin-dependent mechanism. Accordingly, vitronectin mRNA levels were shown to be up-regulated by COUP-TFI by RT-PCR analysis, and COUP-TFI stimulated the mouse vitronectin promoter activity in transient transfection assays. Taken together, these data indicate that COUP-TFI is not simply a global repressor of retinoid functions, but shows a high selectivity for regulating genes involved in cellular adhesion and migration processes that are particularly important for neuronal differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / ultrastructure
  • Base Sequence
  • COUP Transcription Factor I
  • Carcinoma, Embryonal
  • Cell Adhesion
  • Cell Differentiation* / drug effects
  • Cell Movement*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Humans
  • Mice
  • Molecular Sequence Data
  • Neurons / cytology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Point Mutation
  • Promoter Regions, Genetic
  • Sequence Homology, Amino Acid
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Transcriptional Activation
  • Transfection
  • Tretinoin / pharmacology
  • Tumor Cells, Cultured
  • Vitronectin / genetics
  • Vitronectin / metabolism


  • COUP Transcription Factor I
  • DNA-Binding Proteins
  • Extracellular Matrix Proteins
  • NR2F1 protein, human
  • Nr2f1 protein, mouse
  • Transcription Factors
  • Vitronectin
  • Tretinoin