UC San Diego

Nuclear pore complexes (NPCs) are built from 30 different proteins called nucleoporins or Nups. Previous studies have shown that several Nups exhibit cell-type-specific expression and that mutations in NPC components result in tissue-specific diseases. The work presented in this thesis shows that the transmembrane nucleoporin Nup210 is induced and essential for both myogenic and neuronal differentiation. Nup210 is absent in proliferating myoblasts and embryonic stem cells (ESCs) but becomes expressed and incorporated into NPCs during cell differentiation. Preventing Nup210 production by RNAi blocks myogenesis and the differentiation of ESCs into neuroprogenitors. We found that the addition of Nup210 to NPCs does not affect nuclear transport but is required for the induction of genes that are essential for cell differentiation. Our data suggest that Nup210 mediates muscle cell differentiation via its conserved N-terminal domain that extends into the perinuclear space (PNS), since removal of the C-terminal domain, which partially mislocalized Nup210 away from NPCs, efficiently rescued the differentiation defect caused by the knockdown of endogenous Nup210. Furthermore a Nup210 mutant lacking its transmembrane and C-terminal domains that are required for NPC targeting, is sufficient for myoblast differentiation. Overall, these results identify the induction of Nup210 as an essential step in muscle and neuronal differentiation and indicate that Nup210 functions via its large lumenal domain, which may act independently of NPC association and thus appears to function within the NE/ER lumen