Biology subjects

Bonnal, S.

Publications and source records attributed to Bonnal, S..

3 recordsLinked to original sources

bioRxiv2021

Specialization of the photoreceptor transcriptome by Srrm3-dependent microexons is required for outer segment maintenance and vision

Retinal photoreceptors differ in their transcriptomic profiles from other neuronal subtypes, likely as a reflection of their unique cellular morphology and function in the detection of light thorough the ciliary outer segment. We discovered a new layer of this molecular specialization by revealing that the vertebrate retina expresses the largest number of tissue-enriched microexons of all tissue types. A subset of these microexons is included exclusively in photoreceptor transcripts, particularly in genes involved in cilia biogenesis and in vesicle-mediated transport. This microexon program is regulated by Srrm3, a paralog of the neural microexon regulator Srrm4. Despite both proteins positively regulate retina microexons in vitro, only Srrm3 is highly expressed in mature photoreceptors and its deletion in zebrafish results in widespread downregulation of microexon inclusion, severe photoreceptor alterations and blindness. These results shed light into photoreceptors transcriptomic specialization and functionality, uncovering new cell type-specific roles for Srrm3 and microexons with implication for retinal diseases.

systems biology↗

bioRxiv2021

Parallel evolution of a splicing program controlling neuronal excitability in flies and mammals

Neurons draw on alternative splicing for their increased transcriptomic complexity throughout animal phylogeny. To delve into the mechanisms controlling the assembly and evolution of this regulatory layer, we characterized the neuronal microexon program in Drosophila and compared it with that of mammals. We found that in Drosophila, this splicing program is restricted to neurons by the post-transcriptional processing of the enhancer of microexons (eMIC) domain in Srrm234 by Elav and Fne. eMIC deficiency or misexpression leads to widespread neurological alterations largely emerging from impaired neuronal activity, as revealed by a combination of neuronal imaging experiments and cell-type-specific rescues. These defects are associated with the genome-wide skipping of short neural exons, which are strongly enriched in ion channels. Remarkably, we found no overlap of eMIC-regulated exons between flies and mice, illustrating how ancient post-transcriptional programs can evolve independently in different phyla to impact distinct cellular modules while maintaining cell-type specificity.

molecular biology↗

bioRxiv2020

A developmentally programmed splicing failure attenuates the DNA damage response during mammalian zygotic genome activation

The transition from maternal to embryonic transcriptional control is a crucial step in embryogenesis. However, how alternative splicing is regulated during this process and how it contributes to early development is unknown. Using transcriptomic data from pre-implantation stages of human, mouse and cow, we show that the stage of zygotic genome activation (ZGA) exhibits the highest levels of exon skipping diversity reported for any cell or tissue type. Interestingly, much of this exon skipping is temporary, leads to disruptive non-canonical isoforms, and occurs in genes enriched for DNA damage response in the three species. We identified two core spliceosomal components, Snrpb and Snrpd2, as regulators of these patterns. These genes have low maternal expression at the time of ZGA and increase sharply thereafter. Consistently, microinjection of Snrpb/d2 mRNA into mouse zygotes reduces the levels of temporary exon skipping at ZGA, and leads to an increase in etoposide-induced DNA damage response. Altogether, our results suggest that mammalian embryos undergo an evolutionarily conserved and developmentally programmed specific splicing failure at the time of genome activation that attenuates cellular responses to DNA damage at these early stages.

developmental biology↗