Alternative splicing in development

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Science Signaling  17 May 2016:
Vol. 9, Issue 428, pp. ec116
DOI: 10.1126/scisignal.aag1373

A pair of papers published in May show just how important alternative splicing is for the maintenance of muscle health and in the developing brain. Skeletal muscle exhibits a developmental switch in the splice variant of the voltage-gated calcium channel Cav1.1, switching from the higher conducting form Cav1.1e in fetal muscles to the Cav1.1a form with slow activation and low conductance in adult muscles. Aberrant production of the fetal form in adults correlates with severity of myotonic dystrophy type 1, indicating that this switch from high-conducting to low-conducting is clinically important. Sultana et al. engineered mice lacking the exon present in the adult splice variant, resulting in mice with persistent presence of the fetal Cav1.1e into adulthood. The mutant mice had reduced grip strength and ran for shorter times and distances than control mice. Fast and slow muscles isolated from the mutant mice showed reduced contractile force, fatigue, and stimulation-induced fusion frequency. Unlike muscle from control mice, calcium handling during excitation-contraction coupling was altered and involved influx through Cav1.1 in the mutant mice. Furthermore, muscles from the mutant mice exhibited Cav1.1-dependent calcium sparklets, which did not occur in the muscles from the control mice. The persistent presence of Cav1.1e resulted in a change in muscles that are normally “fast” type toward a phenotype more similar to those composed of “slow” type fibers. Of potential relevance to the clinical phenotype in humans, the persistent presence of Cav1.1e altered muscle metabolism and caused mitochondrial damage.

Traunmüller et al. found that the RNA-binding protein and regulator of alternative splicing SLM2 was critical to limit the abundance of AMPA-type glutamate receptors, such that mice lacking SLM2 had an increase in the ratio of AMPA-type to NMDA-type glutamate receptors that resulted in increased synaptic responsiveness, but compromised long-term potentiation (LTP). Genome-wide transcript analysis of hippocampi from control and Slm2 knockout mice revealed only four differentially spliced genes: Nrxn1, -2, and -3, which encode transsynaptic neurexins, and Stxbp5l, which encodes the vesicle fusion protein tomosyn-2. Protein interaction analysis revealed that loss of SLM2 switched the binding partners of neurexin-1. Engineering the missing splice variant of Nrxn1 into the Slm2 knockout rescued the electrophysiological and behavioral phenotypes associated with Slm2 knockout. Thus, alternative splicing plays a key role in synaptic development.

N. Sultana, B. Dienes, A. Benedetti, P. Tuluc, P. Szentesi, M. Sztretye, J. Rainer, M. W. Hess, C. Schwarzer, G. J. Obermair, L. Csernoch, B. E. Flucher, Restricting calcium currents is required for correct fiber type specification in skeletal muscle. Development 143, 1547–1559 (2016). [PubMed]

L. Traunmüller, A. M. Gomez, T.-M. Nguyen, P. Scheiffele, Control of neuronal synapse specification by a highly dedicated alternative splicing program. Science 10.1126/science.aaf2397 (2016). [Abstract]