The faint sausage gene encodes a subunit of the spliceosome-activating Prp19 complex and is required for tracheal branching morphogenesis in Drosophila. The faint sausage gene encodes a subunit of the spliceosome-activating Prp19 complex and is required for tracheal branching morphogenesis in Drosophila

Morphogenesis requires the dynamic regulation of gene expression, including transcription, mRNA maturation and translation. Dysfunction of general components of the splicing machinery can cause surprisingly specific phenotypes, but the basis for these cell-type specific effects is not clear. Here we show that the faint sausage (fas) locus, implicated in epithelial morphogenesis and previously reported to encode a secreted immunoglobulin domain protein, in fact encodes a subunit of the Prp19 complex that is essential for efficient pre-mRNA splicing. Loss of zygotic fas function impairs the efficiency of splicing, associated with widespread retention of introns in mature mRNAs and dramatic changes in gene expression. Surprisingly, despite these general effects, zygotic fas mutants show specific defects in tracheal cell migration. Zygotic fas function becomes essential during late embryogenesis when maternally supplied splicing factors decline. We propose that tracheal branching, which relies on dynamic changes in gene expression, is particularly sensitive for efficient spliceosome function. Our results provide an entry point to study functions of splicing during organogenesis and provide a better understanding of specific disease phenotypes associated with mutations in general splicing factors.

形态发生（Morphogenesis）需要对基因表达进行动态调控，涵盖转录（transcription）、mRNA成熟（mRNA maturation）及翻译（translation）等过程。剪接机器（splicing machinery）的通用组分功能异常，竟可引发极具特异性的表型，但此类细胞类型特异性效应的分子基础迄今仍不明晰。本研究证实，此前被认为编码分泌型免疫球蛋白结构域蛋白、且与上皮形态发生相关的faint sausage (fas) 基因座，实则编码Prp19复合物（Prp19 complex）的一个亚基——该复合物对于高效的前信使RNA（pre-mRNA）剪接至关重要。合子型fas功能缺失会降低剪接效率，表现为成熟mRNA中内含子（introns）广泛滞留，并伴随基因表达的显著改变。令人意外的是，尽管存在这些全局性影响，合子型fas突变体仍表现出气管细胞迁移（tracheal cell migration）的特异性缺陷。当母源供给的剪接因子水平下降时，合子型fas功能在胚胎发生（embryogenesis）晚期变得不可或缺。我们推测，依赖基因表达动态变化的气管分支（tracheal branching）过程，对高效的剪接体（spliceosome）功能尤为敏感。本研究结果为探究器官发生（organogenesis）过程中剪接的功能提供了新的切入点，也有助于更深入理解与通用剪接因子突变相关的特异性疾病表型。