Cytoplasmic pool of U1 spliceosome protein SNRNP70 shapes the axonal transcriptome and regulates motor connectivity

Abstract

Regulation of pre-mRNA splicing and polyadenylation plays a profound role in neurons by diversifying the proteome and modulating gene expression in response to physiological cues. Although most of the pre-mRNA processing is thought to occur in the nucleus, numerous splicing regulators are also found in neurites. Here, we show that U1-70K/SNRNP70, a component of the major spliceosome, localizes in RNA-associated granules in zebrafish axons. We identify the extra-nuclear SNRNP70 as an important regulator of motor axonal growth, nerve-dependent acetylcholine receptor (AChR) clustering, and neuromuscular synaptogenesis. This cytoplasmic pool has a protective role for a limited number of transcripts regulating their abundance and trafficking inside axons. Moreover, non-nuclear SNRNP70 regulates splice variants of transcripts such as agrin, thereby controlling synapse formation. Our results point to an unexpected, yet essential, function of non-nuclear SNRNP70 in axonal development, indicating a role of spliceosome proteins in cytoplasmic RNA metabolism during neuronal connectivity.

Keywords: Z+agrn; alternative splicing; mRNA processing; mRNA stability; mRNA transport; motor neurons; neurodegenerative diseases; neuromuscular junction; ribonucleoprotein complexes; synaptic connectivity.