Abstract:
Cohesin, a chromatin-associated protein complex with four core subunits (Smc1a, Smc3, Rad21 and either Stag1 or 2), has a central role in cell proliferation and gene expression in metazoans. Human developmental disorders termed \'cohesinopathies\' are characterized by germline variants of cohesin or its regulators that do not entirely eliminate cohesin function. However, it is not clear whether mutations in individual cohesin subunits have independent developmental consequences. Here, we show that zebrafish rad21 or stag2b mutants independently influence embryonic tailbud development. Both mutants have altered mesoderm induction, but only homozygous or heterozygous rad21 mutation affects cell cycle gene expression. stag2b mutants have narrower notochords and reduced Wnt signaling in neuromesodermal progenitors as revealed by single-cell RNA sequencing. Stimulation of Wnt signaling rescues transcription and morphology in stag2b, but not rad21, mutants. Our results suggest that mutations altering the quantity versus composition of cohesin have independent developmental consequences, with implications for the understanding and management of cohesinopathies.
摘要:
Cohesin,具有四个核心亚基的染色质相关蛋白复合物(Smc1a,Smc3、Rad21和Stag1或2),在后生动物的细胞增殖和基因表达中起着核心作用。称为“粘附蛋白病”的人类发育障碍的特征是粘附蛋白或其调节剂的种系突变,不能完全消除粘附蛋白的功能。然而,尚不清楚单个粘附素亚基中的突变是否具有独立的发育后果。在这里,我们表明斑马鱼rad21或stag2b突变体独立影响胚胎尾芽发育。两种突变体都改变了中胚层的诱导,但只有纯合或杂合rad21突变影响细胞周期基因表达。stag2b突变体在神经中胚层祖细胞中具有较窄的脊索和减少的Wnt信号,如单细胞RNA测序所揭示的。Wnt信号的刺激挽救stag2b的转录和形态,但不是rad21突变体.我们的结果表明,改变粘附分子数量与组成的突变具有独立的发育后果,对该病的理解和管理具有重要意义。