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Updated: Jul 16, 2026

Analysis of Retinoic Acid-induced Neural Differentiation of Mouse Embryonic Stem Cells in Two and Three-dimensional Embryoid Bodies
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Analysis of Retinoic Acid-induced Neural Differentiation of Mouse Embryonic Stem Cells in Two and Three-dimensional Embryoid Bodies

Published on: April 22, 2017

CSK controls retinoic acid receptor (RAR) signaling: a RAR-c-SRC signaling axis is required for neuritogenic

Nandini Dey1, Pradip K De, Mu Wang

  • 1Section of Pediatric Hematology/Oncology, Department of Pediatrics, Aflac Cancer Center and Blood Disorders Services, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30022, USA.

Molecular and Cellular Biology
|February 28, 2007
PubMed

Insights

This study reveals that cytoplasmic SRC kinase is essential for retinoic acid (RA) receptor (RAR) signaling, impacting neuronal differentiation. CSK negatively regulates this pathway, highlighting a new extranuclear role for RAR signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Retinoic acid (RA) signaling through retinoic acid receptors (RARs) is crucial for neuronal differentiation.
  • The role of cytoplasmic SRC kinase (c-SRC) in RAR signaling has not been previously established.
  • CSK is known to negatively regulate SRC family kinases (SFKs).

Purpose of the Study:

  • To investigate the role of c-SRC in retinoic acid receptor (RAR) signaling during neuronal differentiation.
  • To determine the regulatory mechanism of CSK on RAR-mediated neurite outgrowth.
  • To elucidate the interaction between RAR and c-SRC.

Main Methods:

  • Overexpression of CSK in LA-N-5 cells.
  • Analysis of RA-mediated neurite outgrowth.
  • Assessment of RAC1 activation.
  • Immunofluorescence staining and confocal microscopy for c-SRC and RARgamma colocalization.
  • Surface plasmon resonance and coimmunoprecipitation to confirm RAR-SRC binding.

Main Results:

  • CSK overexpression inhibited RA-induced neurite outgrowth and c-SRC activation.
  • CSK blocked the activation of RAC1, a downstream effector.
  • c-SRC and RARgamma were found to colocalize in the cytoplasm.
  • Direct, ligand-dependent binding between RAR and c-SRC was confirmed in vitro and in vivo.
  • CSK inhibited the RAR-RA-dependent activation of c-SRC and neurite outgrowth.

Conclusions:

  • c-SRC is required for RAR signaling and RA-induced neuronal differentiation.
  • A novel extranuclear, nongenomic signaling pathway involving RAR-c-SRC interaction is negatively regulated by CSK.
  • Transcriptional signaling via RA-RAR is necessary but insufficient for complex neuronal differentiation, with extranuclear signaling playing a critical role.

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