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Updated: Feb 7, 2026
Describing a Transcription Factor Dependent Regulation of the MicroRNA Transcriptome
Published on: June 15, 2016
Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome
Katherine A Donovan1,2, Jian An1,2, Radosław P Nowak1,2
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States.
Abstract:
In historical attempts to treat morning sickness, use of the drug thalidomide led to the birth of thousands of children with severe birth defects. Despite their teratogenicity, thalidomide and related IMiD drugs are now a mainstay of cancer treatment; however, the molecular basis underlying the pleiotropic biology and characteristic birth defects remains unknown. Here we show that IMiDs disrupt a broad transcriptional network through induced degradation of several C2H2 zinc finger transcription factors, including SALL4, a member of the spalt-like family of developmental transcription factors. Strikingly, heterozygous loss of function mutations in SALL4 result in a human developmental condition that phenocopies thalidomide-induced birth defects such as absence of thumbs, phocomelia, defects in ear and eye development, and congenital heart disease. We find that thalidomide induces degradation of SALL4 exclusively in humans, primates, and rabbits, but not in rodents or fish, providing a mechanistic link for the species-specific pathogenesis of thalidomide syndrome.
Insights
Thalidomide and related drugs cause birth defects by degrading developmental transcription factors like SALL4. This mechanism explains species-specific effects and links SALL4 mutations to similar human developmental conditions.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Thalidomide and related immunomodulatory drugs (IMiDs) are used in cancer treatment despite historical teratogenicity.
- The molecular mechanisms behind thalidomide's pleiotropic effects and birth defects remain unclear.
Purpose of the Study:
- To elucidate the molecular basis of thalidomide-induced birth defects.
- To investigate the role of C2H2 zinc finger transcription factors in IMiD action.
Main Methods:
- Investigated the impact of IMiDs on transcriptional networks.
- Identified SALL4 as a key target degraded by IMiDs.
- Analyzed human genetic data for SALL4 loss-of-function mutations.
Main Results:
- IMiDs induce degradation of multiple C2H2 zinc finger transcription factors, including SALL4.
- Heterozygous loss-of-function mutations in SALL4 cause human developmental defects mirroring thalidomide syndrome.
- Thalidomide-induced SALL4 degradation is species-specific (humans, primates, rabbits) but not observed in rodents or fish.
Conclusions:
- SALL4 degradation is a key mechanism underlying thalidomide's teratogenicity.
- SALL4 mutations provide a genetic model for thalidomide-induced birth defects.
- Species-specific SALL4 sensitivity explains the differential pathogenesis of thalidomide syndrome.
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