Rucker, T. | bioRxiv Science

bioRxiv2026

Transposable Element insertions Repurpose Immune Endonucleases as Drivers of Reproductive Isolation in Mice

The emergence of reproductive barriers between closely related populations is a fundamental step in speciation, yet the underlying genetic mechanisms remain poorly understood in mammals. Here we resolve the DDK syndrome, a long-standing model of hybrid incompatibility in mice, by showing that two independent retrotransposon insertions rewire immune Schlafen endoribonuclease genes expression, causing hybrid embryo death. A DDK-private MERVL element drives ectopic oocyte expression of Slfn1, while an intragenic ETn/MusD insertion in incompatible strains is associated with zygotic Slfn15 expression. SLFN1-SLFN15 heterodimerization constitutively activates tRNA ribonuclease activity, leading to global translation inhibition, and integrated stress response activation. Abolishing SLFN1 catalytic activity or SLFN15 expression rescues syndromic embryo development. Our findings uncover a previously unrecognized speciation mechanism in which transposable elements repurpose immune effectors as drivers of postzygotic reproductive isolation.

developmental biology↗

bioRxiv2022

TAOK2β represses translation via phosphorylation of eEF2 and ameliorates exaggerated protein synthesis in a mouse model of 16p11.2 microdeletion-driven autism

Microdeletions in the 16p11.2 region of the human genome are frequently associated with autism spectrum disorders (ASDs), but how these genomic rearrangements cause ASD remains unclear. Here, we reveal that TAOK2{beta}, a protein isoform encoded by the human TAOK2 gene located in the 16p11.2 locus, regulates mRNA translation. To identify key functional interaction partners of TAOK2{beta}, we performed proteomic screening from Neuro-2a (N2a) cells, mouse cortices, and cultured neurons. This revealed translation factors as a major class of enriched interacting proteins. Consistently, TAOK2{beta} is present in mouse cortical polyribosomes and cortices from Taok2 knockout mice show increased ribosome density on mRNAs and enhanced protein synthesis. Several lines of evidence support an effect of TAOK2{beta} on translation elongation via phosphorylation of eukaryotic elongation factor (eEF2). TAOK2 can directly phosphorylate eEF2 on Threonine 56 and this phosphorylation is reduced in cortices from Taok2 knockout mice. TAOK2{beta} WT overexpression increased eEF2 phosphorylation levels and reduced protein synthesis, whereas a kinase-dead allele of TAOK2{beta} showed opposite effects. Finally, we show that cortices from the mouse model of the human 16p11.2 microdeletion have increased polysome/monosome (P/M) ratios and protein synthesis, phenocopying Taok2 loss of function. Importantly, defective translation phenotypes observed in the mouse 16p11.2 microdeletion model of ASD could be normalized either by reintroducing Taok2 in vivo or by delivering TAOK2{beta} to cortical neurons derived from 16p11.2 microdeletion mice. Our results uncover a critical role of TAOK2{beta} as a regulator of protein synthesis and support the idea that translational control is a common endpoint of ASD-associated signaling pathways.

neuroscience↗