Researchers at the Institute for Bioengineering of Catalonia (IBEC) and the University Medical Center Göttingen have achieved, for the first time, in vivo light-activated auditory stimulation without the need for genetic manipulation. This new light-controlled drug, capable of triggering the neural pathways involved in hearing, can contribute to improving the spectral resolution of cochlear implants used by people with profound hearing loss or deafness.

One million people around the world use cochlear implants (CIs), surgically implanted devices which restore sound perception in case of deafness. Microphones convert sound into electric signals that then directly stimulate the auditory nerve in the cochlea, the structure in the inner ear involved in hearing.

Although CIs can recover understanding of speech in the quiet, users have difficulty following conversations in background noise and limited music appreciation due to their limited spectral resolution. This is caused by the spread of electrical stimulation in the liquid-filled cochlea. Stimulation with light has been proposed as an alternative, for example with optogenetics and light-emitting CIs pioneered by the University Medical Center Göttingen (UMCG).

In collaboration with the Institute for Bioengineering of Catalonia (IBEC), an alternative route to optogenetics has been developed to couple light and electrical activity in the neurons without using genetic manipulation. The researchers have developed a photopharmacological agent that chemically attaches to a neuroreceptor protein like a ‘molecular prosthesis’ and readily activates the neurons when illuminated. It was used to activate auditory neurons with light at kilohertz frequencies in adult gerbils and could ultimately contribute to improving the spectral resolution of cochlear implants.

Alternative splicing expands transcriptome diversity in eukaryotes. Impacting most human genes, alternative splicing can famously generate multiple protein isoforms from the same gene. However, it can also be used to control the final amounts of functional proteins, by generating non-productive transcripts that effectively downregulate gene expression.

Here, we investigated how alternative splicing was regulated during the first stages of embryonic development in mammals, when a major molecular event occurs: the awakening of the zygotic genome. Whereas the first steps are fully driven by the mRNAs and proteins deposited by the mother, the zygotic genome starts to be transcribed soon and takes full control of embryogenesis.

We found that the cells in the embryo undergoing zygotic genome activation (ZGA) exhibit the highest levels of exon skipping of all cell and tissue types (including the brain). However, this striking transcriptomic diversity is temporary, lasting only 1-2 cell cycles (Fig. 1a). Moreover, it mainly leads to the production of unproductive transcripts (Fig. 1b), effectively killing genes enriched for DNA damage responses (DDR) at ZGA, in line with the low reparative response of early embryos.

Remarkably, this is due to a developmentally programmed splicing failure (Fig. 1d): during oogenesis some core spliceosomal components (Snrpb/d2) are not deposited at sufficient levels and splicing for some genes fails when zygotic transcription starts. However, these core components are themselves strongly transcribed at ZGA, and thus their levels recover after 1-2 stages, giving rise to the peak-like splicing patterns.

This model makes a simple prediction: if we express Snrpb/d2 earlier, we should be able to "rescue" the failed splicing patterns (Fig. 1d). This is what we saw. Moreover, this also increased DDR in those "rescued" embryos.

In summary, we uncovered an evolutionarily conserved, developmentally programmed splicing failure during ZGA, which modules DDR. What we have not yet answered is: why would the embryo boycott itself at ZGA? Future research will tell...