TorsinA is essential for the timing and localization of neuronal nuclear pore complex biogenesis

Abstract

Nuclear pore complexes (NPCs) regulate information transfer between the nucleus and cytoplasm. NPC defects are linked to several neurological diseases, but the processes governing NPC biogenesis and spatial organization are poorly understood. Here, we identify a temporal window of strongly upregulated NPC biogenesis during neuronal maturation. We demonstrate that the AAA+ protein torsinA, whose loss of function causes the neurodevelopmental movement disorder DYT-TOR1A (DYT1) dystonia, coordinates NPC spatial organization during this period without impacting total NPC density. Using a new mouse line in which endogenous Nup107 is Halo-Tagged, we find that torsinA is essential for correct localization of NPC formation. In the absence of torsinA, the inner nuclear membrane buds excessively at sites of mislocalized, nascent NPCs, and NPC assembly completion is delayed. Our work implies that NPC spatial organization and number are independently regulated and suggests that torsinA is critical for the normal localization and assembly kinetics of NPCs.

Coordinating nucleoporin condensation and nuclear pore complex assembly

“…Remarkably, these herniations are quite analogous to those observed in yeast upon mutation of Brl1 [65], in that they contain several Nups at an electron-dense neck that presumably resembles an immature NPC but lack the cytosolic subunit Nup358 that would only be added after the INM/ONM fusion has occurred [42, 73,94]. Similar observations were made in mouse models [81,95]. Furthermore, torsin-deficient cells can be grown in large quantities, enabling a compositional analysis of nuclear envelope herniations by combining classical subcellar fractionation with comparative proteomics.…”

“…fruit flies, mouse neurons, and human cell lines [73,[77][78][79][80][81]. Torsins are unusual members of the AAA+ ATPase protein superfamily, which is composed of ATPases associated with diverse cellular activities [78].…”

“…In mouse models, deletion of torsinA during a developmental window causes cells of the central nervous system to develop nuclear envelope herniations and the onset of dystonic symptoms [80,91]. Importantly, a burst of NPC biogenesis was observed in developing mouse neurons [81,92], making neurons an attractive model Fig. 2.…”

“…Interestingly, both the mislocalization of NPC components to the cytoplasm and the disturbed spatial distribution are observed upon loss of torsins in mouse neurons as well [81]. Given that the chromatin-and torsin-associated INM protein LAP1 was tied to nuclear envelope dynamics recently [118,119], it will be important to scrutinize the spatial organization of inside-out NPC biogenesis.…”