Ctip2 is a dynamic regulator of epidermal proliferation and differentiation by integrating EGFR and Notch signaling

J Cell Sci. 2012 Dec 1;125(Pt 23):5733-44. doi: 10.1242/jcs.108969. Epub 2012 Sep 26.


Epidermal morphogenesis results from a delicate balance between keratinocyte proliferation and differentiation, and this balance is perturbed upon deletion of transcription factor Ctip2. Here we demonstrate that Ctip2, in a cell autonomous manner, controls keratinocyte proliferation and cytoskeletal organization, and regulates the onset and maintenance of differentiation in keratinocytes in culture. Ctip2 integrates keratinocyte proliferation and the switch to differentiation by directly and positively regulating EGFR transcription in proliferating cells and Notch1 transcription in differentiating cells. In proliferative cells, the EGFR promoter is occupied by Ctip2, whereas Ctip2 is only recruited to the Notch1 promoter under differentiating conditions. Activation of EGFR signaling downregulates Ctip2 at the transcript level, whereas high calcium signaling triggers SUMOylation, ubiquitination and proteasomal degradation of Ctip2 at the protein level. Together, our findings demonstrate a novel mechanism(s) of Ctip2-mediated, coordinated control of epidermal proliferation and terminal differentiation, and identify a pathway of negative feedback regulation of Ctip2 during epidermal development.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cell Proliferation
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Epidermal Cells*
  • Epidermis / metabolism*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Immunoblotting
  • Immunohistochemistry
  • Immunoprecipitation
  • In Situ Nick-End Labeling
  • In Vitro Techniques
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Mice
  • Mice, Knockout
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • Bcl11b protein, mouse
  • Receptors, Notch
  • Repressor Proteins
  • Tumor Suppressor Proteins
  • ErbB Receptors