SAM68-Specific Splicing Is Required for Proper Selection of Alternative 3' UTR Isoforms in the Nervous System

Yoko Iijima; Masami Tanaka; Satoko Suzuki; David Hauser; Masayuki Tanaka; Chisa Okada; Masatoshi Ito; Noriko Ayukawa; Yuji Sato; Masato Ohtsuka; Peter Scheiffele; Takatoshi Iijima

doi:10.1016/j.isci.2019.11.028

SAM68-Specific Splicing Is Required for Proper Selection of Alternative 3' UTR Isoforms in the Nervous System

iScience. 2019 Dec 20:22:318-335. doi: 10.1016/j.isci.2019.11.028. Epub 2019 Nov 16.

Authors

Affiliations

¹ Tokai University Institute of Innovative Science and Technology, 143 Shimokasuya, Isehara City, Kanagawa 259-1193, Japan; Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, School of Medicine, Tokai University, 143, Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
² Tokai University Institute of Innovative Science and Technology, 143 Shimokasuya, Isehara City, Kanagawa 259-1193, Japan.
³ Biozentrum, University of Basel, Klingelbergstrasse 50-70, Basel 4056, Switzerland.
⁴ The Support Center for Medical Research and Education, Tokai University, 143 Shimokasuya, Isehara City, Kanagawa 259-1193, Japan.
⁵ Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, School of Medicine, Tokai University, 143, Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
⁶ Tokai University Institute of Innovative Science and Technology, 143 Shimokasuya, Isehara City, Kanagawa 259-1193, Japan; Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, School of Medicine, Tokai University, 143, Shimokasuya, Isehara, Kanagawa 259-1193, Japan. Electronic address: takatoshi.iijima@tokai-u.jp.

Abstract

Neuronal alternative splicing is a core mechanism for functional diversification. We previously found that STAR family proteins (SAM68, SLM1, SLM2) regulate spatiotemporal alternative splicing in the nervous system. However, the whole aspect of alternative splicing programs by STARs remains unclear. Here, we performed a transcriptomic analysis using SAM68 knockout and SAM68/SLM1 double-knockout midbrains. We revealed different alternative splicing activity between SAM68 and SLM1; SAM68 preferentially targets alternative 3' UTR exons. SAM68 knockout causes a long-to-short isoform switch of a number of neuronal targets through the alteration in alternative last exon (ALE) selection or alternative polyadenylation. The altered ALE usage of a novel target, interleukin 1 receptor accessory protein (Il1rap), results in remarkable conversion from a membrane-bound type to a secreted type in Sam68^KO brains. Proper ALE selection is necessary for IL1RAP neuronal function. Thus the SAM68-specific splicing program provides a mechanism for neuronal selection of alternative 3' UTR isoforms.

Keywords: Biological Sciences; Molecular Biology; Molecular Mechanism of Gene Regulation; Molecular Neuroscience; Neuroscience.