Sizing and shaping the nucleus: mechanisms and significance

Abstract

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.

Figure 1. Mechanisms of nuclear size and shape regulation

The central diagram depicts the major cellular components involved in regulating nuclear morphology. The blue boxes around the edge depict specific examples where mechanisms determining nuclear size and/or shape have been identified. (a) In Xenopus egg extracts, lamin B3 (LB3) depletion reduces nuclear size [13], while supplementing extract with LB3 increases the rate of NE expansion [14]. (b) Mislocalization of LAP2 or addition of a dominant negative fragment of LAP2 to Xenopus egg extract inhibits nuclear growth [19,20]. (c) Expression of nesprin-2 lacking the ABD increases nuclear size, while expression of nesprin-2-mini decreases nuclear size [21,22]. (d) Altered LBR and lamin A (LA) expression in neutrophils affects nuclear lobulation [30,31]. (e) Progerin expression leads to the formation of misshapen nuclei that can be rescued with farnesylation inhibitors [34]. (f) Altered expression of Arabidopsis thaliana Nup136 affects both nuclear size and elongation [44,45]. (g) Stem cell differentiation is associated with acquisition of a perinuclear actin cap that regulates nuclear morphology through LINC and lamina interactions [49]. (h) ECM stiffness modulates nuclear shape [53].

Figure 2. Cell cycle events that influence nuclear morphology

(a) REEP3/4 are required to clear ER membrane from metaphase chromatin. Failure to do so leads to intranuclear membrane invaginations extending into the interphase nucleus. Image adapted with permission from [56]. (b) Post-mitotic suppression of microtubule (red) polymerization by Dppa2 (green) is required for the formation of a nucleus with normal morphology. Chromatin is shown in blue. Image adapted with permission from [57]. (c) Depletion of LEM4 in C. elegans leads to misshapen, multi-lobed nuclei [58]. (d) Depletion of the ubiquitin ligase SCF^Slimb leads to increased condensin II activity in interphase, chromatin compaction, and deformed nuclear morphology [70]. (e) The brambleberry protein (red) is required for karyomere fusion during early zebrafish development. In the absence of brambleberry (bmb) multiple micronuclei form. Image adapted with permission from [71]. (f) The process of micronuclear formation and disruption is depicted. A micronucleus forms around a lagging chromosome at the end of mitosis. During interphase, disorganization of the nuclear lamina leads to NE collapse, chromatin compaction, and intercalation of tubular ER. Image adapted with permission from [104].