UC San Diego

Nuclear pore proteins (Nups) form the only channels on the nuclear envelope that allow macromolecule transport between the cytoplasm and the nucleoplasm. Initial studies in the unicellular organism yeast have confirmed that deletions and/or mutations of multiple Nups result in deficiency in bulk transport between cellular compartments and subsequently lethality. Recent investigations regarding multicellular organisms, however, have revealed that mutations in Nups are often linked to cell-type specific defects and diseases. Therefore, there might be cell-type specific functions of Nups, for example in the context of differentiation. One potential cell-type specific function of Nups could be related to the regulation of genes that are activated in a cell-type dependent manner. Such hypothesis stems from the observation that microscopically, Nups appear to selectively interact with active genomic regions. To test this hypothesis, chromatin immunoprecipitation experiments for Nup98 have been performed in multiple cell types, including human cells at different stages of neural differentiation. It has been found that the patterns of Nup98-genome interaction are highly cell-type specific in the neural differentiation system. Further functional studies have demonstrated a role of Nup98 in regulating the expression of a cohort of genes active during neural development. As an alternative approach to investigate into the potential cell-type dependent behavior of Nups, dynamics of Nups were analyzed at different stages of muscle differentiation by live cell imaging. One Nup, Nup50, was found to exhibit decreased dynamics upon differentiation, serving as the first example of a Nup that has altered dynamics during development. Kifc1, a kinesin-superfamily protein that is predicted to be a nuclear motor, was found to confer the higher dynamics of Nup50 by physical interaction before differentiation. Upon differentiation, Kifc1 is degraded, which could explain the decrease in Nup50 mobility. Knocking down Nup50 decreased efficiency of muscle differentiation, whereas knocking down Kifc1 accelerated muscle differentiation. This suggests that Nup50 is differentially regulated during muscle development and is functionally important for differentiation. Together these studies revealed previously unidentified roles of Nup98 and Nup50 in differentiation, which might shed light on the cell-type specific diseases related to Nup mutations