Cereblon controls the timing of muscle differentiation in Ciona embryos

Abstract

Thalidomide has a dark history as a teratogen, but in recent years it has been shown to function as a chemotherapeutic agent. Thalidomide binds cereblon, a component of E3 ubiquitin ligase complex and modifies its degradation targets. Despite these insights, remarkably little is known about the normal function of cereblon in development. Here, we employ the simple proto-vertebrate model, Ciona intestinalis, to address this question. We observed a "hotspot" of Crbn expression in the developing tail muscles and identify its enhancer containing both Myod activator sites and a Snail repressive element. Overexpression of Crbn in tail muscles decreases expression of contractility genes. We suggest that this reduction is due to premature degradation of Tbx6. Drug inhibition studies using lenalidomide, a derivative of thalidomide, lead to a striking increase of Crbn expression. This autofeedback regulation could be induced by neomorphic degradation of Snail, contributing to the efficacy of lenalidomide in treating metastatic melanoma. In summary, our analysis of Crbn suggests that its normal function in Ciona is to time expression of contractility genes during muscle differentiation thereby ensuring coordination of tail morphogenesis and hatching of swimming tadpoles.