果蝇唐氏综合症细胞黏附分子（Dscam）和脊椎动物原钙粘蛋白（Pcdh）是单基因位点产生蛋白同源异构体多样性的两个经典例子。黑腹果蝇Dscam基因通过可变剪接方式可产生多达38 016种同源异构体，而脊椎动物Pcdhs通过选择性启动子实现蛋白多样性。我们前期研究揭示了竞争性RNA二级结构调控Dscam互斥剪接的机制（NSMB，2011；Nat Commun，2012；RNA，2016）。最近，我们发现螯肢动物Dscam转录本5'端出人意料的多样性和复杂性，研究表明是通过可变启动子和可变剪接相结合的机制产生的，这为理解果蝇Dscam和脊椎动物Pcdhs的功能相似性提供了重要线索（Nat Commun，已接受）。在此基础上，我们将阐明选择性启动子如何与可变剪接协同激活5'端外显子表达的具体机制，建立5'端多样性调控的新模型，探明Dscam 5'端高度多样性在神经发育等重要生理过程中的作用。

Drosophila Dscam1 and vertebrate clustered protocadherins (Pcdhs) are two classic examples of the extraordinary isoform diversity from a single genomic locus, and both have remarkable functional similarity. Dscam1 encodes 38,016 distinct isoforms via mutually exclusive splicing in D. melanogaster, while the vertebrate clustered Pcdhs utilize alternative promoters to generate isoform diversity. We previously indicated that competing RNA structures played an impotant role in mutually exclusive splicing (Nat Struct Mol Biol, 2011; Nat Commun, 2012; RNA, 2016). Recently, we unexpectedly found extraordinary 5' isoform diversity and complexity of the Chelicerata Dscam transcripts, which were achieved through a combination of alternating promoter and alternative splicing (Nat Commun, 2016, accepted). Our findings have important implications for understanding the functional similarities between Drosophila Dscam1 and vertebrate Pcdhs. Next, we will elucidate the mechanism how alternative promoters cooperate with alternative splicing to control the selection of alternative exons at the 5' variable region, and propose a novel model for the regulation of 5' isoform diversity. Additionally, we will reveal the biological roles of the Dscam 5' isoform diversity, particularly in nervous system development.