Cereblon influences the timing of muscle differentiation in Ciona tadpoles

Proc Natl Acad Sci U S A. 2023 Oct 24;120(43):e2309989120. doi: 10.1073/pnas.2309989120. Epub 2023 Oct 19.

Abstract

Thalidomide has a dark history as a teratogen, but in recent years, its derivates have been shown to function as potent chemotherapeutic agents. These drugs bind cereblon (CRBN), the substrate receptor of an E3 ubiquitin ligase complex, and modify its degradation targets. Despite these insights, remarkably little is known about the normal function of cereblon in development. Here, we employ Ciona, a simple invertebrate chordate, to identify endogenous Crbn targets. In Ciona, Crbn is specifically expressed in developing muscles during tail elongation before they acquire contractile activity. Crbn expression is activated by Mrf, the ortholog of MYOD1, a transcription factor important for muscle differentiation. CRISPR/Cas9-mediated mutations of Crbn lead to precocious onset of muscle contractions. By contrast, overexpression of Crbn delays contractions and is associated with decreased expression of contractile protein genes such as troponin. This reduction is possibly due to reduced Mrf protein levels without altering Mrf mRNA levels. Our findings suggest that Mrf and Crbn form a negative feedback loop to control the precision of muscle differentiation during tail elongation.

Keywords: Cereblon; Ciona; Mrf; muscle development; proteasomal degradation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins
  • Ciona intestinalis* / genetics
  • Ciona intestinalis* / metabolism
  • Larva / genetics
  • Larva / metabolism
  • Muscles* / metabolism
  • Peptide Hydrolases* / genetics
  • Peptide Hydrolases* / metabolism
  • Thalidomide / adverse effects
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Carrier Proteins
  • Peptide Hydrolases
  • Thalidomide
  • Transcription Factors
  • Ubiquitin-Protein Ligases