Cereblon influences the timing of muscle differentiation in Ciona tadpoles

Juanjuan Long, Andrea Mariossi, Chen Cao, Zhongying Mo, Joel W. Thompson, Michael S. Levine, Laurence A. Lemaire

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article numbere2309989120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number43
DOIs
StatePublished - 2023

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Cereblon
  • Ciona
  • Mrf
  • muscle development
  • proteasomal degradation

Fingerprint

Dive into the research topics of 'Cereblon influences the timing of muscle differentiation in Ciona tadpoles'. Together they form a unique fingerprint.

Cite this