ZFIN ID: ZDB-PUB-110110-12
CtBP2 Downregulation during Neural Crest Specification Induces Expression of Mitf and REST, Resulting in Melanocyte Differentiation and Sympathoadrenal Lineage Suppression
Liang, H., Fekete, D.M., and Andrisani, O.
Date: 2011
Source: Molecular and cellular biology   31(5): 955-970 (Journal)
Registered Authors: Fekete, Donna Marie
Keywords: none
MeSH Terms:
  • Animals
  • Carrier Proteins/genetics
  • Carrier Proteins/metabolism
  • Cell Differentiation*
  • Cell Line
  • Cyclic AMP/metabolism
  • Cyclic AMP/pharmacology
  • Cyclic AMP Response Element-Binding Protein/metabolism
  • Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases/metabolism
  • Down-Regulation
  • Melanocytes/cytology*
  • Melanocytes/drug effects
  • Mice
  • Microphthalmia-Associated Transcription Factor/biosynthesis*
  • Neural Crest/cytology
  • Neural Crest/drug effects
  • Neural Crest/growth & development*
  • Protein Serine-Threonine Kinases/genetics
  • Protein Serine-Threonine Kinases/metabolism
  • Repressor Proteins/biosynthesis*
  • Repressor Proteins/metabolism*
  • Sympathetic Nervous System/cytology
  • Sympathetic Nervous System/drug effects
  • Sympathetic Nervous System/growth & development*
  • Transcription, Genetic/drug effects
  • Zebrafish/embryology
  • Zebrafish Proteins/biosynthesis*
  • Zebrafish Proteins/metabolism*
PubMed: 21199918 Full text @ Mol. Cell. Biol.
Trunk neural crest (NC) cells differentiate to neurons, melanocytes and glia. In NC cultures, cAMP induces melanocyte differentiation while suppressing neuronal sympathoadrenal lineage, depending on signal intensity. Melanocyte differentiation requires activation of CREB and cAMP-dependent protein kinase A (PKA), but the role of PKA is not understood. We demonstrate in NC cultures cAMP induced transcription of microphthalmia-associated transcription factor (Mitf) and RE-1 silencing transcription factor (REST), both Wnt-regulated genes. In NC cultures and zebrafish, knockdown of the co-repressor of Wnt-mediated transcription C-terminal binding protein2 (CtBP2), but not CtBP1, de-repressed Mitf and REST expression and enhanced melanocyte differentiation. cAMP in NC and B16 melanoma cells decreased CtBP2 protein levels, while inhibition of PKA or proteasome rescued CtBP2 degradation. Interestingly, knockdown of homeodomain-interacting protein kinase2 (HIPK2), a CtBP stability modulator, increased CtBP2 levels, suppressed expression of Mitf, REST and melanocyte differentiation, and increased neuronal gene expression and sympathoadrenal lineage differentiation. We conclude cAMP/PKA via HIPK2 promotes CtBP2 degradation leading to Mitf and REST expression. Mitf induces melanocyte specification, and REST suppresses neuron-specific gene expression and the sympathoadrenal lineage. Our studies identify a novel role for REST in NC cell differentiation and suggest cross-talk between cAMP and Wnt signaling in NC lineage specification.