Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome

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 C ₂H ₂ 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.

eLife digest

Thalidomide was sold in the 1950s and 1960s as a sedative and anti-nausea medication for pregnant women suffering from morning sickness. Studies in mice and other animals had suggested thalidomide was safe and led some countries to allow the drug to be used in humans. By 1961, it became clear that thalidomide use by pregnant women led to serious birth defects, and the drug was removed from the market. By then, thalidomide had caused birth defects in over 10,000 babies, a tragedy that has been described as the biggest man-made medical disaster in human history. It led many countries to adopt tougher standards for drug safety.

Thalidomide and similar drugs are now used with great success to treat leprosy and various blood cancers. But questions remain about exactly how the drugs work and how they cause birth defects like shortened arms and legs. Previous studies have shown that thalidomide binds to a protein called cereblon, which marks other proteins for destruction and removal from the cell. Thalidomide hijacks cereblon and causes it to tag the wrong proteins.

To learn more about how thalidomide causes birth defects, Donovan et al. treated human embryonic stem cells and cancer cells with thalidomide and related drugs. Analyzing the proteins inside the cells revealed that the drugs caused dramatic reductions in the amount of a protein called SALL4, which is essential for limb development. It was already known that mutations in the gene that produces SALL4 cause two conditions called Duane Radial Ray syndrome and Holt-Oram syndrome. Both conditions can result in birth defects like those seen in babies exposed to thalidomide.

As well as showing that thalidomide-hijacked cereblon marks SALL4 for destruction, Donovan et al. also reveal why mice do not develop birth defects when exposed to thalidomide. This is because genetic differences make the mouse cereblon proteins unable to tag SALL4. Researchers could now build on these results to develop safer versions of thalidomide that do not target SALL4 while still successfully treating leprosy and cancers.