Neuronal SAM68 differentially regulates alternative last exon splicing and ensures proper synapse development and function

Mohamed Darwish, Masatoshi Ito, Yoko Iijima, Akinori Takase, Noriko Ayukawa, Satoko Suzuki, Masami Tanaka, Kanae Komori, Daisuke Kaida, Takatoshi Iijima*

*この論文の責任著者

研究成果: ジャーナルへの寄稿学術論文査読

抄録

Alternative splicing in the 3′UTR of mammalian genes plays a crucial role in diverse biological processes, including cell differentiation and development. SAM68 is a key splicing regulator that controls the diversity of 3′UTR isoforms through alternative last exon (ALE) selection. However, the tissue/cell type-specific mechanisms underlying the splicing control at the 3′ end and its functional significance remain unclear. Here, we show that SAM68 regulates ALE splicing in a dose-dependent manner and the neuronal splicing is differentially regulated depending on the characteristics of the target transcript. Specifically, we found that SAM68 regulates interleukin-1 receptor-associated protein splicing through the interaction with U1 small nuclear ribonucleoprotein. In contrast, the ALE splicing of protocadherin-15 (Pcdh15), a gene implicated in several neuropsychiatric disorders, is independent of U1 small nuclear ribonucleoprotein but modulated by the calcium/calmodulin-dependent protein kinase signaling pathway. We found that the aberrant ALE selection of Pcdh15 led to a conversion from a membrane-bound to a soluble isoform and consequently disrupted its localization into excitatory and inhibitory synapses. Notably, the neuronal expression of the soluble form of PCDH15 preferentially affected the number of inhibitory synapses. Moreover, the soluble form of PCDH15 interacted physically with α-neurexins and further disrupted neuroligin-2-induced inhibitory synapses in artificial synapse formation assays. Our findings provide novel insights into the role of neuron-specific alternative 3′UTR isoform selections in synapse development.

本文言語英語
論文番号105168
ジャーナルJournal of Biological Chemistry
299
10
DOI
出版ステータス出版済み - 2023/10

ASJC Scopus 主題領域

  • 生化学
  • 分子生物学
  • 細胞生物学

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