SAM68-regulated ALE selection of Pcdh15 maintains proper synapse development and function

Author:

Darwish Mohamed,Ito Masatoshi,Takase Akinori,Ayukawa Noriko,Suzuki Satoko,Tanaka Masami,Iijima Yoko,Iijima Takatoshi

Abstract

AbstractThousands of mammalian genes encode alternatively spliced isoforms in their 3’ untranslated region (3’UTR). Alternative 3’UTR diversity may contribute to several neurological processes in developing and adult brains. SAM68 is the key splicing regulator for the diversity of neuronal 3’UTR isoforms through alternative last exon (ALE) selection. However, the mechanisms underlying the control of splicing at the 3’ end and its function in the nervous system remain unclear. Here, we show that neuronal SAM68-dependent ALE splicing is regulated depending on its target transcripts. For example, the selection of the ALE ofprotocadherin-15(Pcdh15), a gene implicated in Usher syndrome and several neuropsychiatric disorders, is largely dependent on the expression of SAM68, partially regulated via the CaMK pathway, but independent of the U1 small nuclear ribonucleoprotein. We found that the aberrant ALEs ofPcdh15caused membrane-to-soluble isoform conversion of the produced protein and disrupted its localization into excitatory and inhibitory synapses. In addition, the neuronal expression of the soluble form of PCDH15 (sPCDH15) preferentially affected the number of inhibitory synapses. sPCDH15 further reduced neuroligin-2-induced inhibitory, but not excitatory, synapses in artificial synapse formation assays. Our findings provide insights into the role of alternative 3’UTR isoform selections in synapse development.

Publisher

Cold Spring Harbor Laboratory

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