Svetlana Doroshev

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.

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.

A widespread dogma asserts that life could not have emerged without biopolymers – RNA and proteins. However, the widely acknowledged implausibility of a spontaneous appearance and proliferation of these complex molecules in primordial messy chemistry casts doubt on this scenario. A proposed alternative is “Lipid-First”, based on the evidence that lipid assemblies may spontaneously emerge in heterogeneous environments, and are shown to undergo growth and fission, and to portray autocatalytic self-copying. What seems undecided is whether lipid assemblies have protein-like capacities for stereospecific interactions, a sine qua non of life processes. This Viewpoint aims to alleviate such doubts, pointing to growing experimental evidence that lipid aggregates possess dynamic surface configurations capable of stereospecific molecular recognition. Such findings help support a possible key role of lipids in seeding life's origin.