Sauerwald Julia, Soneson Charlotte, Robinson Mark D, Luschnig Stefan
Institute of Neurobiology, University of Münster, Badestrasse 9, 48149 Münster, Germany.
Cluster of Excellence EXC 1003, Cells in Motion (CiM), 48149 Münster, Germany.
Development. 2017 Feb 15;144(4):657-663. doi: 10.1242/dev.144535. Epub 2017 Jan 13.
Morphogenesis requires the dynamic regulation of gene expression, including transcription, mRNA maturation and translation. Dysfunction of the general mRNA splicing machinery can cause surprisingly specific cellular phenotypes, but the basis for these effects is not clear. Here, we show that the () locus, which is implicated in epithelial morphogenesis and has previously been reported to encode a secreted immunoglobulin domain protein, in fact encodes a subunit of the spliceosome-activating Prp19 complex, which is essential for efficient pre-mRNA splicing. Loss of zygotic function globally impairs the efficiency of splicing, and is associated with widespread retention of introns in mRNAs and dramatic changes in gene expression. Surprisingly, despite these general effects, zygotic mutants show specific defects in tracheal cell migration during mid-embryogenesis when maternally supplied splicing factors have declined. We propose that tracheal branching, which relies on dynamic changes in gene expression, is particularly sensitive for efficient spliceosome function. Our results reveal an entry point to study requirements of the splicing machinery during organogenesis and provide a better understanding of disease phenotypes associated with mutations in general splicing factors.
形态发生需要对基因表达进行动态调控，包括转录、mRNA成熟和翻译。一般mRNA剪接机制的功能障碍可导致惊人的特异性细胞表型，但其作用基础尚不清楚。在这里，我们表明，与上皮形态发生有关且先前报道编码一种分泌型免疫球蛋白结构域蛋白的（）基因座，实际上编码剪接体激活Prp19复合物的一个亚基，该亚基对有效的前体mRNA剪接至关重要。合子功能的丧失会全面损害剪接效率，并与mRNA中内含子的广泛保留以及基因表达的显著变化有关。令人惊讶的是，尽管有这些普遍影响，但在胚胎中期，当母源供应的剪接因子减少时，合子突变体在气管细胞迁移中表现出特定缺陷。我们认为，依赖基因表达动态变化的气管分支对有效的剪接体功能特别敏感。我们的结果揭示了一个研究器官发生过程中剪接机制需求的切入点，并能更好地理解与一般剪接因子突变相关的疾病表型。
