PRDM paralogs antagonistically balance Wnt/β-catenin activity during craniofacial chondrocyte differentiation

Development. 2022 Feb 15;149(4):dev200082. doi: 10.1242/dev.200082. Epub 2022 Feb 24.


Cranial neural crest cell (NCC)-derived chondrocyte precursors undergo a dynamic differentiation and maturation process to establish a scaffold for subsequent bone formation, alterations in which contribute to congenital birth defects. Here, we demonstrate that transcription factor and histone methyltransferase proteins Prdm3 and Prdm16 control the differentiation switch of cranial NCCs to craniofacial cartilage. Loss of either paralog results in hypoplastic and disorganized chondrocytes due to impaired cellular orientation and polarity. We show that these proteins regulate cartilage differentiation by controlling the timing of Wnt/β-catenin activity in strikingly different ways: Prdm3 represses whereas Prdm16 activates global gene expression, although both act by regulating Wnt enhanceosome activity and chromatin accessibility. Finally, we show that manipulating Wnt/β-catenin signaling pharmacologically or generating prdm3-/-;prdm16-/- double mutants rescues craniofacial cartilage defects. Our findings reveal upstream regulatory roles for Prdm3 and Prdm16 in cranial NCCs to control Wnt/β-catenin transcriptional activity during chondrocyte differentiation to ensure proper development of the craniofacial skeleton.

Keywords: Craniofacial; Mecom/Evi1; Mouse; Neural crest; Prdm16; Prdm3; Wnt/β-catenin; Zebrafish.

Publication types

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

MeSH terms

  • Animals
  • Cartilage / cytology
  • Cartilage / metabolism
  • Cell Differentiation*
  • Chondrocytes / cytology
  • Chondrocytes / metabolism
  • Chondrogenesis
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Developmental
  • MDS1 and EVI1 Complex Locus Protein / deficiency
  • MDS1 and EVI1 Complex Locus Protein / genetics
  • MDS1 and EVI1 Complex Locus Protein / metabolism*
  • Mice
  • Mice, Knockout
  • Neural Crest / cytology
  • Neural Crest / metabolism
  • Regulatory Sequences, Nucleic Acid
  • Skull / cytology
  • Skull / metabolism
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway / genetics*
  • Zebrafish
  • Zebrafish Proteins / deficiency
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*
  • beta Catenin / metabolism


  • Chromatin
  • DNA-Binding Proteins
  • MDS1 and EVI1 Complex Locus Protein
  • Wnt Proteins
  • Zebrafish Proteins
  • beta Catenin
  • prdm16 protein, zebrafish