Summary Early Xenopus laevis embryogenesis is a robust system for investigating mechanisms of developmental timing. After a series of rapid cell divisions with concomitant reductions in cell size, the first major developmental transition is the midblastula transition (MBT), when zygotic transcription begins and cell cycles elongate [1-3]. While the maintenance of a constant nuclear-to-cytoplasmic (N/C) volume ratio is a conserved cellular property [4-7], it has long been recognized that the N/C volume ratio changes dramatically during early Xenopus development [8]. We investigated how changes in nuclear size and the N/C volume ratio during early development contribute to the regulation of MBT timing. While previous studies suggested a role for the N/C volume ratio in MBT timing [1, 9-13], none directly tested the effects of altering nuclear size. In this study, we first quantify blastomere and nuclear sizes in X. laevis embryos, demonstrating that the N/C volume ratio increases prior to the MBT. We then manipulate nuclear volume in embryos by microinjecting different nuclear scaling factors, including import proteins, lamins, and reticulons. Using this approach, we show that increasing the N/C volume ratio in pre-MBT embryos leads to premature activation of zygotic gene transcription and early onset of longer cell cycles. Conversely, decreasing the N/C volume ratio delays zygotic transcription and leads to additional rapid cell divisions. While the DNA-to-cytoplasmic ratio has been implicated in MBT timing [1, 9-18], our data show that nuclear size also contributes to the regulation of MBT timing, demonstrating the functional significance of nuclear size during development.

The size and shape of the nucleus are tightly regulated, indicating the physiological significance of proper nuclear morphology, yet the mechanisms and functions of nuclear size and shape regulation remain poorly understood. Correlations between altered nuclear morphology and certain disease states have long been observed, most notably many cancers are diagnosed and staged based on graded increases in nuclear size. Here we review recent studies investigating the mechanisms regulating nuclear size and shape, how mitotic events influence nuclear morphology, and the role of nuclear size and shape in subnuclear chromatin organization and cancer progression.

Changes in nuclear size have long been used by cytopathologists as an important parameter to diagnose, stage, and prognose many cancers. Mechanisms underlying these changes and functional links between nuclear size and malignancy are largely unknown. Understanding mechanisms of nuclear size regulation and the physiological significance of proper nuclear size control will inform the interplay between altered nuclear size and oncogenesis. In this chapter we review what is known about molecular mechanisms of nuclear size control based on research in model experimental systems including yeast, Xenopus, Tetrahymena, Drosophila, plants, mice, and mammalian cell culture. We discuss how nuclear size is influenced by DNA ploidy, nuclear structural components, cytoplasmic factors and nucleocytoplasmic transport, the cytoskeleton, and the extracellular matrix. Based on these mechanistic insights, we speculate about how nuclear size might impact cell physiology and whether altered nuclear size could contribute to cancer development and progression. We end with some outstanding questions about mechanisms and functions of nuclear size regulation.

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Background:The nuclear lamina is a meshwork of intermediate lamin filaments lining the inner nuclear membrane. Results: Altering lamin concentrations in Xenopus extracts, embryos, and cultured mammalian cells affects nuclear size. Conclusion: Nuclear size is sensitive to lamin levels in Xenopus and mammalian cells. Significance: Lamin expression patterns may contribute to changes in nuclear size during normal development and carcinogenesis.