Getting nuclear size just right – emerging mechanisms regulating nuclear scaling and morphology

It has been known for over a century that nuclear size generally scales with cell size, and nuclear morphology aberrations have long been used for disease diagnosis and prognosis, most notably in cancers. Over the past several decades, an extensive catalog of activities and proteins that affect nuclear size have been identified. However, fundamental questions remain about the physical mechanisms that control nuclear growth and size, and their regulation by known effectors of nuclear morphology. Studies have begun to elucidate the forces that act on and within cells and the biophysical properties of the cytoplasm and nucleoplasm, providing new insights that have directly informed mechanisms of nuclear size regulation or hinted at new mechanisms that await experimental testing. In this Review, we focus on recent studies of nuclear size regulation, with an emphasis on how nuclear size scales to cell size and the roles of the biophysical properties of the cell, nuclear mechanics and chromatin in nuclear scaling. We also discuss how interorganellar contacts and novel nuclear structures might impact nuclear size, new insights into the connection between nuclear size and disease, and recently developed experimental systems and approaches that might be used to address outstanding questions in the field.