Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544.
Bristol Myers Squibb, San Diego, CA 92121.
Proc Natl Acad Sci U S A. 2023 Oct 24;120(43):e2309989120. doi: 10.1073/pnas.2309989120. Epub 2023 Oct 19.
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 , a simple invertebrate chordate, to identify endogenous Crbn targets. In is specifically expressed in developing muscles during tail elongation before they acquire contractile activity. expression is activated by Mrf, the ortholog of MYOD1, a transcription factor important for muscle differentiation. CRISPR/Cas9-mediated mutations of lead to precocious onset of muscle contractions. By contrast, overexpression of 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 mRNA levels. Our findings suggest that Mrf and Crbn form a negative feedback loop to control the precision of muscle differentiation during tail elongation.
沙利度胺作为一种致畸剂有着黑暗的历史，但近年来，其衍生物已被证明具有很强的化疗作用。这些药物与 cereblon（CRBN）结合，cereblon 是一种 E3 泛素连接酶复合物的底物受体，并修饰其降解靶标。尽管有了这些见解，但 cereblon 在发育中的正常功能仍知之甚少。在这里，我们利用一种简单的无脊椎脊索动物来鉴定内源性 Crbn 靶标。 在 中， 在尾巴伸长过程中肌肉发育时特异性表达，然后才获得收缩活性。 的表达被 Mrf 激活，Mrf 是 MYOD1 的同源物，是肌肉分化的重要转录因子。CRISPR/Cas9 介导的 突变导致肌肉收缩过早发生。相比之下， 的过表达会延迟收缩，并与收缩蛋白基因（如肌钙蛋白）的表达减少有关。这种减少可能是由于 Mrf 蛋白水平降低而不改变 mRNA 水平所致。我们的研究结果表明，Mrf 和 Crbn 形成负反馈回路，以控制尾巴伸长过程中肌肉分化的精确性。
