SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate

Nat Chem Biol. 2018 Oct;14(10):981-987. doi: 10.1038/s41589-018-0129-x. Epub 2018 Sep 6.


Targeted protein degradation via small-molecule modulation of cereblon offers vast potential for the development of new therapeutics. Cereblon-binding therapeutics carry the safety risks of thalidomide, which caused an epidemic of severe birth defects characterized by forelimb shortening or phocomelia. Here we show that thalidomide is not teratogenic in transgenic mice expressing human cereblon, indicating that binding to cereblon is not sufficient to cause birth defects. Instead, we identify SALL4 as a thalidomide-dependent cereblon neosubstrate. Human mutations in SALL4 cause Duane-radial ray, IVIC, and acro-renal-ocular syndromes with overlapping clinical presentations to thalidomide embryopathy, including phocomelia. SALL4 is degraded in rabbits but not in resistant organisms such as mice because of SALL4 sequence variations. This work expands the scope of cereblon neosubstrate activity within the formerly 'undruggable' C2H2 zinc finger family and offers a path toward safer therapeutics through an improved understanding of the molecular basis of thalidomide-induced teratogenicity.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • Gene Expression Regulation*
  • Homozygote
  • Humans
  • Immunohistochemistry
  • Induced Pluripotent Stem Cells
  • Ligands
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Peptide Hydrolases / chemistry*
  • Peptide Hydrolases / genetics
  • Proteolysis
  • Rabbits
  • Teratogens / chemistry*
  • Testis / metabolism
  • Thalidomide / chemistry*
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Zinc Fingers


  • Adaptor Proteins, Signal Transducing
  • CRBN protein, human
  • Crbn protein, mouse
  • DNA-Binding Proteins
  • Ligands
  • Nerve Tissue Proteins
  • SALL4 protein, human
  • Sall4 protein, mouse
  • Teratogens
  • Transcription Factors
  • Thalidomide
  • Ubiquitin-Protein Ligases
  • Peptide Hydrolases
  • ZFP91 protein, human