Doroshev, S. | bioRxiv Science

bioRxiv2026

RTTN moonlights beyond the centrosome to control ribosome biogenesis and tRNA modification in human brain organoids

RTTN (rotatin) is a centrosomal protein mutated in severe malformations of cortical development, yet how its dysfunction disrupts human corticogenesis has remained unclear. Here, we show that RTTN has an unrecognized function at the core of the translation machinery. Using human telencephalic and hippocampal organoids carrying distinct RTTN alleles, together with single-cell and bulk transcriptomics, polysome profiling, and tRNA pseudouridine sequencing, we find that RTTN is enriched in cycling first-trimester neural progenitors and physically associates with ribosome-biogenesis and RNA-processing factors. RTTN mutations impair rRNA biogenesis and polysome assembly, reduce cytoplasmic ribosome density and nascent protein synthesis, and remodel the tRNA pseudouridylation landscape through both a PUS7L-dependent variable-arm signature and a broader RTTN-specific defect. These translational deficits are accompanied by prolonged mitosis, reduced entry into S-phase, and impaired interkinetic nuclear migration in mutant progenitors. Our findings redefine RTTN as a regulator of ribosome homeostasis and mRNA translation and implicate defective translational capacity as a driver of RTTN-associated microcephaly. Graphical AbstractRTTN sustains ribosome and tRNA homeostasis in human neural progenitors; its mutation disrupts mRNA translation, stalling progenitor proliferation and interkinetic nuclear migration, and driving cortical malformation and growth failure. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/744412v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@16124aaorg.highwire.dtl.DTLVardef@ae23f7org.highwire.dtl.DTLVardef@bb588forg.highwire.dtl.DTLVardef@1b35028_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

SUN5 forms a regular protein lattice reinforcing the sperm head-tail junction

Linker of nucleo- and cytoskeleton (LINC) complexes reside in the nuclear envelope, the double-membrane surrounding the nucleus, where they establish a physical bridge between nucleus and cytoplasm. LINC complexes are conserved throughout the tree of life and are present in most nucleated cell types in the human body. They play a major role in signal transduction across the nuclear envelope and in regulating nuclear morphology. One of the most drastic nuclear remodeling events occurs during sperm maturation. Multiple sperm-specific LINC complexes are essential for the sperm cell to adapt its highly streamlined nuclear shape and to secure a stable connection between sperm head and tail. Importantly, mutations in the LINC protein SUN5 result in head-tail detachment, also referred to as acephalic spermatozoa syndrome, rendering affected individuals infertile. Here, using super-resolution fluorescence microscopy we find that sperm-specific SUN5 localizes to the base of the human sperm head and by applying in situ cryo-electron tomography we find an extensive two-dimensional lattice in the nuclear envelope at this region. Moreover, this lattice appears to maintain a consistent close apposition between the inner and outer nuclear membranes. Further structural analysis supports a model in which SUN5 forms trimers that laterally interact at the outer nuclear membrane. Overall, this study sheds light on nuclear envelope organization in the highly streamlined sperm cell, providing mechanistic insights into uniform nuclear envelope spacing maintained by a LINC lattice and rationalizing disruptive effects of SUN5 mutations on the sperm head-tail junction.

cell biology↗