Cereblon influences the timing of muscle differentiation in <i>Ciona</i> tadpoles.

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 <i>Ciona</i>, a simple invertebrate chordate, to identify endogenous Crbn targets. In <i>Ciona, Crbn</i> is specifically expressed in developing muscles during tail elongation before they acquire contractile activity. <i>Crbn</i> expression is activated by Mrf, the ortholog of MYOD1, a transcription factor important for muscle differentiation. CRISPR/Cas9-mediated mutations of <i>Crbn</i> lead to precocious onset of muscle contractions. By contrast, overexpression of <i>Crbn</i> 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 <i>Mrf</i> mRNA levels. Our findings suggest that Mrf and Crbn form a negative feedback loop to control the precision of muscle differentiation during tail elongation.