RBPMS2 is a conserved regulator of alternative splicing that promotes myofibrillar organization and optimal calcium handling in cardiomyocytes

Akerberg, A. A.; Trembley, M.; Butty, V.; Schwertner, A.; Zhou, L.; Beerens, M.; Liu, X.; Mahamdeh, M.; Yuan, S.; MacRae, C.; Nguyen, C.; Pu, W. T.; Burns, C. E.; Burns, C. G.

doi:10.1101/2021.03.08.434502

bioRxiv · 10.1101/2021.03.08.434502

RBPMS2 is a conserved regulator of alternative splicing that promotes myofibrillar organization and optimal calcium handling in cardiomyocytes

Akerberg, A. A.·Trembley, M.·Butty, V.·Schwertner, A.·Zhou, L.·Beerens, M.·Liu, X.·Mahamdeh, M.·Yuan, S.·MacRae, C.·Nguyen, C.·Pu, W. T.·Burns, C. E.·Burns, C. G.

View original source ↗Export metadata ↓

Abstract

RationaleThe identification of novel cardiomyocyte-intrinsic factors that support heart function will expand the number of candidate genes and therapeutic options for heart failure, a leading cause of death worldwide. ObjectiveTo identify and characterize conserved regulators of cardiomyocyte function. Methods and ResultsWe report that the RNA-binding protein RBPMS2 is required for myofibril organization and the regulation of intracellular calcium dynamics in both zebrafish embryos and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). A differential expression screen in zebrafish uncovered enrichment of rbpms2 paralogs, rbpms2a and rbpms2b, in the myocardium. Double knock-out (rbpms2-null) embryos suffer from compromised ventricular filling during the relaxation phase of the cardiac cycle, which significantly reduces cardiac output. Whole transcriptome sequencing and validation studies revealed differential alternative splicing of several genes linked to cardiomyopathies in humans, including myosin binding protein C3 (mybpc3) and phospholamban (pln), consistent with a role in causing the observed ventricular deficiencies. Further, RBPMS2-null hiPSC-CMs exhibit myofibril and calcium handling defects that are highly analogous to those observed in the rbpms2-null zebrafish ventricle. ConclusionsTaken together, our data identify RBPMS2 as a conserved and essential regulator of alternative splicing that is required for myofibrillar organization and optimal calcium handling from zebrafish to humans.

Source connections

Published article ↗

Explore related subjects

developmental biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Akerberg, A. A., Trembley, M., Butty, V., Schwertner, A., Zhou, L., Beerens, M., Liu, X., Mahamdeh, M., Yuan, S., MacRae, C., Nguyen, C., Pu, W. T., Burns, C. E., Burns, C. G.. 2021-03-09. RBPMS2 is a conserved regulator of alternative splicing that promotes myofibrillar organization and optimal calcium handling in cardiomyocytes. https://doi.org/10.1101/2021.03.08.434502

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Dynamic mechanical sorting biases niche occupancy and lineage outcome during development of bilayered glandular epithelia

Tissue compartmentalization into basal and luminal domains is a hallmark of glandular epithelia, yet how fate boundaries are established and stabilized during dynamic morphogenesis remains a major unresolved question. Here, using mouse embryonic explants, organoids, quantitative live imaging and genetic perturbations, we show that basal-luminal compartmentalization is not maintained by fixed boundaries, but through continuous positional corrections. We show that differences in cellular adhesion and actomyosin contractility drive these positional corrections by promoting active cell sorting. We further find that these mechanical differences influence lineage specification by controlling cell positioning rather than directly instructing cell fate. Before commitment, mosaic, but not uniform, perturbation of cell mechanics alters niche occupancy and biases lineage outcome, indicating that relative mechanical properties determine access to fate-instructive niches. Conversely, perturbation of Notch and YAP remodels compartment-specific mechanical properties and cell-positioning dynamics, revealing a reciprocal coupling between lineage state and mechanical sorting. Conservation of this mechanism across four glandular epithelia of distinct origins and functions identifies dynamic mechanical sorting as a general strategy for maintaining robust tissue compartmentalization during the extensive growth and cellular rearrangements of branching morphogenesis.

developmental biology↗

bioRxiv2026

Unbiased lineage tracing across the adipose organ decouples developmental origin from anatomical and transcriptomic identities

The developmental origins of individual adipose depots and whether embryonic lineage dictates adult function remain unresolved. Here, we apply in utero CRISPR-mediated barcoding lineage tracing to construct the first unbiased clonal map of adipose organ development in mice. The developmental hierarchy we uncover challenges several conventions. Remarkably, interscapular brown fat, used as the prototypical brown fat, is the most developmentally isolated brown fat; depots sharing Myf5/Pax3 lineage markers fail to cluster together; mesenteric white fat shares unexpected high clonal ancestry with brown fats despite a radically divergent transcriptome; and subcutaneous white adipose tissues converge transcriptomically despite distant developmental origins. These findings call for a reinterpretation of single-marker lineage tracing data across the adipose organ and propose that adipose depot identity is not solely encoded by embryonic lineage but is substantially shaped by the anatomical niche.

developmental biology↗

bioRxiv2026

Age-dependent mechanical stress underlies unexpected vestibular differentiation and regeneration patterns

Loss of inner-ear sensory hair cells (HCs) is a major cause of hearing and balance disorders. Promoting HC regeneration offers a potential therapeutic strategy, but regenerative capacity is limited in adult mammals and declines rapidly during early postnatal development in mice. HCs can regenerate through trans-differentiation of neighboring supporting cells in a process controlled by Notch mediated lateral inhibition. However, the factors underlying the decrease in regeneration capacity are poorly understood. Here, we combine live imaging with single-HC ablation in mouse vestibular explants to track the dynamics of HC development and regeneration. We reveal unexpected age-dependent deviations from the classical lateral inhibition model, in which new HCs differentiate adjacent to existing HCs. We find that mechanical stress changes with age and that perturbing it alters the observed differentiation patterns. A mathematical model incorporating local mechanical regulation of Notch signaling captures both HC differentiation and regeneration patterns across ages. Together, these findings identify mechanical stress as a crucial regulator of HC differentiation and support an underlying mechanism in which the interplay between local mechanics and Notch signaling shapes regenerative responses. This coupling offers a framework for understanding the age-dependent decline in HC regeneration and motivates investigation of mechanical regulation as a potential therapeutic target.

developmental biology↗