KASH-domain proteins in nuclear migration, anchorage and other processes

Abstract

The nucleus in eukaryotic cells can move within the cytoplasm, and its position is crucial for many cellular events, including migration and differentiation. Nuclear anchorage and movement can be achieved through association of outer nuclear membrane (ONM) proteins with the three cytoskeletal systems. Two decades ago studies described C. elegans mutants with defects in such events, but only recently has it been shown that the strategies for nuclear positioning are indeed conserved in C. elegans, Drosophila, mammals and potentially all eukaryotes. The integral ONM proteins implicated in these processes thus far all contain a conserved Klarsicht/ANC-1/Syne homology (KASH) domain at their C-terminus that can associate with Sad1p/UNC-84 (SUN)-domain proteins of the inner nuclear membrane within the periplasmic space of the nuclear envelope (NE). The complex thus formed is responsible not only for association with cytoplasmic elements but also for the integrity of the NE itself. Journal of Cell Science 5022 region and residues that lie within the PS, and a cytoplasmic N-terminus that does not show sequence similarity to any known protein (McGee et al., 2006). UNC-84 contains several potential transmembrane domains and a C-terminal region that is homologous to the yeast protein Sad1p and, accordingly, is called the Sad1p/UNC-84 (SUN) domain (Malone et al., 1999;McGee et al., 2006). The localization of UNC-84 to the INM is not dependent upon its SUN domain but rather on the presence of nuclear lamins, which probably interact with its Nterminus (Lee et al., 2002). Deletion of UNC-84, mutations in the UNC-84 SUN domain or mutations within the UNC-83 KASH domain can prevent the localization of UNC-83 at the ONM (McGee et al., 2006;Starr et al., 2001), presumably because of a loss of direct interaction between the UNC-83 KASH and UNC-84 SUN domains within the PS (McGee et al., 2006) (Fig. 2). This explains why the nuclear migration defects in unc-83 and unc-84 mutant worms are very similar (Malone et al., 1999). Curiously, UNC-83 is present at the NE in a limited number of cell types (including P, hyp7, intestinal, pharyngeal and uterine cells), unlike UNC-84, which is localized at the NE in nearly all cells (Starr et al., 2001).UNC-83 and UNC-84 were originally proposed to tether the nucleus to centrosomes, which was hypothesized to drive nuclear migration (Malone et al., 1999;Reinsch and Gonczy, 1998); however, later studies showed a normal association between the centrosomes and nuclei in unc-83 and unc-84 mutant cells whose nuclei fail to migrate (Lee et al., 2002;Starr et al., 2001). The proteins that interact with the N-terminus of UNC-83 to facilitate nuclear migration have not been identified. Recently, another ONM protein, was shown to mediate an association between the centrosomes and Journal of Cell Science 119 (24) the nucleus in C. elegans. In zygote defective (zyg)-12 mutant worms, the centrosome detachment defect in the developing embryo results in death as a consequence of chromosome segregation defects (...

Nuclear migration during retinal development

“…Specifically, mutational screens in yeast (Saccharomyces cervisiae and Schizoscharomyces pombe), filamentous fungi (Aspergillus nidulins and Neurospora crassa), nematodes (Caenorhadbitis elegans), and fruit flies (Drosophila melanogaster) have all implicated microtubule-based motors and specific classes of nuclear envelope proteins as essential for nuclear migration and positioning (Morris, 2003;Xiang and Fischer, 2004;Starr and Fischer, 2005;Wilhelmsen et al, 2006). With regard to cytoskeletal motors, cytoplasmic dynein and dynactin are essential for normal nuclear migration in multiple contexts.…”

“…The klarsicht gene was found to encode a protein with a Cterminal domain shared with ANC-1 of C. elegans and Syne/Nesprin proteins of vertebrates (Starr and Fischer, 2005;Wilhelmsen et al, 2006). This motif was termed the KASH domain for Klarsicht, ANC-1, and Syne homology.…”

Communication between the cytoskeleton and the nuclear envelope to position the nucleus

“…5,6 ). Mutations in unc-83 or unc-84 disrupt nuclear migration events in at least three tissues 7-9 while mutations in anc-1 or unc-84 disrupt nuclear anchorage in a wide variety of cells.…”

“…2; for review see 6,[13][14][15]. In general, SUN proteins contain a conserved SUN domain at their C-termini and at least one transmembrane domain.…”

“…2; for review see ref. 6,[13][14][15]. The nuclear envelope bridging model has been refined by four groups who have each concluded that SUN proteins reside in the INM where they function to target and retain KASH proteins to the ONM through a direct interaction.…”