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First published online January 10, 2008
doi: 10.1242/10.1242/jcs.005777

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Shaping the endoplasmic reticulum into the nuclear envelope

Salk Institute for Biological Studies, Molecular and Cell Biology Laboratory, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA

^* Author for correspondence (e-mail: hetzer{at}salk.edu)

Accepted 7 November 2007

	Summary

Top Summary Introduction Tearing apart the nuclear... Reconstitution of the NE... Targeting membranes to chromatin... Membrane reshaping from tubule... Nuclear closure and expansion Perspectives References

 
The nuclear envelope (NE), a double membrane enclosing the nucleus of eukaryotic cells, controls the flow of information between the nucleoplasm and the cytoplasm and provides a scaffold for the organization of chromatin and the cytoskeleton. In dividing metazoan cells, the NE breaks down at the onset of mitosis and then reforms around segregated chromosomes to generate the daughter nuclei. Recent data from intact cells and cell-free nuclear assembly systems suggest that the endoplasmic reticulum (ER) is the source of membrane for NE assembly. At the end of mitosis, ER membrane tubules are targeted to chromatin via tubule ends and reorganized into flat nuclear membrane sheets by specific DNA-binding membrane proteins. In contrast to previous models, which proposed vesicle fusion to be the principal mechanism of NE formation, these new studies suggest that the nuclear membrane forms by the chromatin-mediated reshaping of the ER.

Key words: Nuclear envelope, Endoplasmic reticulum, Membrane sheets, Tubules, DNA-binding membrane proteins, Open mitosis

	Introduction

Top Summary Introduction Tearing apart the nuclear... Reconstitution of the NE... Targeting membranes to chromatin... Membrane reshaping from tubule... Nuclear closure and expansion Perspectives References

 
A central trait of eukaryotic cells is the physical separation of the nuclear genome from the cytoplasm by the nuclear envelope (NE). This barrier is composed of two spheroid membrane sheets, the inner and outer nuclear membranes (INM and ONM), which are evenly separated by 50 nm, generating the perinuclear space (Callan and Tomlin, 1950; Cohen et al., 2002). The INM and ONM are connected at numerous sites, where aqueous channels form between the nucleoplasm and the cytoplasm. These channels are occupied by nuclear pore complexes (NPCs), large protein assemblies that mediate all transport across the NE (Fahrenkrog et al., 2004; Hetzer et al., 2005; Vasu and Forbes, 2001; Wente, 2000; Wozniak and Lusk, 2003).

The NE forms a continuous membrane system with the ER network, which allows molecules to diffuse freely between the perinuclear space and the ER lumen (Voeltz et al., 2002). The functional relationship between the ONM and the rough ER becomes obvious when visualized at the ultrastructural level, ribosomes covering both membranes (Gerace and Burke, 1988; Newport and Forbes, 1987). Despite the lipid continuity between the NE and ER, both the ONM and INM are specialized domains that contain specific integral membrane proteins that are not abundant in ER cisternae. For instance, proteins of the nesprin family specifically localize to the ONM and interact with components of the cytoskeleton and Sun-domain-containing INM proteins (Apel et al., 2000; Mislow et al., 2002; Wilhelmsen et al., 2006; Zhang et al., 2001). The INM contains many integral membrane proteins that provide binding sites for chromatin or the lamina, a protein meshwork that provides structural integrity to the nucleus (Burke and Stewart, 2002; Gruenbaum et al., 2005) (Foisner, 2001; Lusk et al., 2007; Worman and Courvalin, 2000). A recent study identified >60 NE transmembrane proteins (NETs). Although most of these remain uncharacterized, many of those analyzed have been shown to interact with chromatin and/or the nuclear lamina (Schirmer et al., 2003). This suggests NETs may play a vital role in chromatin organization. Furthermore, recent studies suggest that the interactions between the NE and chromatin regulate gene expression (Akhtar and Gasser, 2007; Taddei, 2007). The importance of the NE for cell function is further highlighted by numerous human diseases (Burke and Stewart, 2002) caused by mutations in NE proteins or lamins (Mounkes and Stewart, 2004; Muchir and Worman, 2004; Roux and Burke, 2007; Wilson, 2000; Worman and Courvalin, 2004). This novel class of genetic disorders, referred to as laminopathies or `nuclear envelopathies', include muscular dystrophies, neurodegenerative diseases and progeria (Gruenbaum et al., 2005; Mounkes et al., 2003; Nagano and Arahata, 2000; Pollex and Hegele, 2004).

The overall topology of the NE is evolutionarily conserved; however, different mechanisms have evolved to propagate the nucleus to the daughter cells. In yeasts, the NE is preserved during cell division, and the mitotic spindle forms within the nucleus. After chromosome segregation, the nucleus is divided into two daughter nuclei by a poorly understood fission process (Heath, 1980). By striking contrast, the nuclear membrane of metazoa completely disassembles at the prophase-metaphase transition to allow cytoplasmic microtubules of the mitotic spindle to gain access to condensing chromosomes. Such `open' mitosis require NE reformation after chromosome segregation (Heath, 1980). This is in contrast to the ER network, which remains intact throughout mitosis. Between these extreme cases of open and closed mitosis lies a continuum of mechanisms in which the NE becomes partially permeable (De Souza et al., 2004; Sazer, 2005).

The rapidly growing field of nuclear biology has been covered by many recent reviews. The links between the NE and chromatin (Akhtar and Gasser, 2007; Hetzer et al., 2005; Holmer and Worman, 2001; Shaklai et al., 2007; Taddei et al., 2004), the nuclear lamina (Gruenbaum et al., 2003; Gruenbaum et al., 2005; Hutchison, 2002), and cytoskeleton (D'Angelo and Hetzer, 2006; Tzur et al., 2006) have been covered extensively and are not discussed further here. In this Commentary, we summarize new work on membrane restructuring events during metazoan NE formation, focusing mainly on the reorganization of the ER that leads to the formation of the spheroid nuclear membrane sheets and nuclear expansion.

View larger version (17K): [in this window] [in a new window]   Fig. 1. Metazoan cells undergo open mitosis. U2OS cells were transfected with a construct encoding the first 65 aa of Sec61 conjugated to (GFP-Sec61) and H2BtdTomato, and imaged in real time using spinning disk confocal microscopy throughout mitosis. Following chromatin condensation (prophase) the NE is torn apart and absorbed into the ER (pro-metaphase). When the chromosomes align on the metaphase plate there is little or no contact between chromosomes and the membranes of the ER (metaphase). The tubule tips of the ER first contact the chromatin during chromosome segregation (anaphase). The NE is reformed during cytokenisis (daughter cells). Scale bar, 10 µm.

	Tearing apart the nuclear envelope in mitosis

Top Summary Introduction Tearing apart the nuclear... Reconstitution of the NE... Targeting membranes to chromatin... Membrane reshaping from tubule... Nuclear closure and expansion Perspectives References

NE disassembly is facilitated by components of the cytoskeleton. Connected to the NE, the dynein-dynactin motor complex generates tension by moving along microtubules, rupturing the NE when a critical tension is reached (Beaudouin et al., 2002; Salina et al., 2002) (reviewed in Burke and Ellenberg, 2002). As the NE is torn apart, NETs detach from chromatin and redistribute into the ER (see below). The microtubule-NE interactions continue to pull NE fragments away from chromosomes towards the centrosome, clearing virtually all the metaphase chromatin surface of membrane (Beaudouin et al., 2002) (Fig. 1). Recently, NEBD in Xenopus egg extracts was shown to involve microtubules and the small GTPase Ran (Joseph, 2006; Muhlhausser and Kutay, 2007). Besides its well-known function in nucleocytoplasmic transport (Hetzer et al., 2002; Sazer and Dasso, 2000), Ran also regulates spindle assembly. Interestingly, the role of Ran in NEBD seems to be transport independent and therefore it may act directly as a mitotic regulator (Dasso, 2002; Di Fiore et al., 2004; Hetzer et al., 2002).

The fate of disassembled NE components after NEBD has been studied both in vitro and in vivo. NPCs disassemble into stable subcomplexes, which are released into the cytoplasm. The transmembrane nucleoporins POM121 and gp210, as well as all NETs analyzed to date (LBR, Lap2β, emerin, Sun1, Sun2 and nurim), are absorbed by the mitotic ER (Beaudouin et al., 2002; Anderson and Hetzer, 2007; Daigle et al., 2001; Ellenberg et al., 1997) (our unpublished data). Furthermore, immunofluorescence analysis has demonstrated that endogenous NE membrane proteins colocalize with components of the ER in cells fixed in metaphase (Yang et al., 1997). The ER network might therefore serve as a `mitotic storage site' for NE components, and the ER could be the precursor membrane for NE formation (Burke and Ellenberg, 2002). Indeed, this possibility was first raised several decades ago, following EM analysis of mitotic cells, which revealed ER membranes contacting chromatin during NE formation (Robbins and Gonatas, 1964).

This interpretation of live-cell imaging and EM data has been met with some skepticism in the face of a different model based on EM studies and biochemical data (Collas and Courvalin, 2000). In this model, the NE disassembles into NE vesicles that do not mix with the ER network. This idea was supported by the finding that membrane vesicles enriched in NE proteins can be isolated from embryonic extracts from Xenopus, sea urchin and Drosophila embryos (Collas et al., 1996; Drummond et al., 1999; Ulitzur et al., 1997; Vigers and Lohka, 1991). Indeed, NE formation in vitro can be initiated by the binding of a specific vesicle population to chromatin (Hetzer et al., 2000; Hetzer et al., 2001; Newport, 1987; Sasagawa et al., 1999). The COPI coatamer complex, which exhibites Nup153-dependent recruitment to the NE in mitosis, has been implicated in NEBD, and COP-coated vesicles can be detected at the disassembling NE together with ER tubules (Cotter et al., 2007; Liu et al., 2003). The role of the COPI complex in NEBD remains to be determined, but note that the morphology of NE vesicles observed in the in vitro assembly reactions is different from that of COPI vesicles (Rabouille and Klumperman, 2005). Those NE vesicles therefore probably represent fragmented ER that is broken apart during membrane purification (Wiese et al., 1997).

If NE vesicles in cell extracts indeed represent artificially fragmented ER, it is not difficult to reconcile the two opposing models (Burke and Ellenberg, 2002; Hetzer et al., 2005). NE proteins that are redistributed into the mitotic ER might preferentially localize to different domains inside the ER network, which is composed of large sheets and tubules. ER proteins such as Sec61β, a translocator subunit, and the tubule-shaping protein reticulon 4a are known to localize to different ER subdomains: low-curvature cisternal sheets and high-curvature tubules, respectively (Voeltz et al., 2006). Similarly, the nucleoporins POM121 (Daigle et al., 2001) and Ndc1 (Mansfeld et al., 2006; Stavru et al., 2006), which in interphase localize to the curved membranes at the nuclear pore, might be present at higher concentrations in tubules, whereas INM proteins such as Sun1 and Sun2 might be enriched in ER cisternal sheets (Shibata et al., 2006). Cell fractionation results in a heterogeneous vesicle population, and NE components may end up in specific vesicles. We therefore favor the notion that the NE is formed from the ER rather than a distinct mitotic vesicle population.

	Reconstitution of the NE and the ER in vitro

Top Summary Introduction Tearing apart the nuclear... Reconstitution of the NE... Targeting membranes to chromatin... Membrane reshaping from tubule... Nuclear closure and expansion Perspectives References

 
Much of current knowledge about the molecular mechanisms of NE formation has come from studies using Xenopus egg extracts (Lohka and Masui, 1983; Newport, 1987). Egg extracts, which contain large stockpiles of disassembled NE components (Newport and Spann, 1987), can be used efficiently to assemble nuclei that are capable of nucleocytoplasmic transport, DNA replication, as well as NEBD (Gant and Wilson, 1997; Hetzer et al., 2002; Sheehan et al., 1988). In vitro, nuclei can be assembled around a variety of chromatin or DNA substrates (Forbes et al., 1983; Heald et al., 1996; Lohka and Masui, 1983), and as discussed above membrane isolated from disrupted Xenopus eggs can be used to reconstitute the ER network (Dreier and Rapoport, 2000). Although these extracts provide a unique experimental system to study ER and NE reconstitution, it has to be emphasized, however, that the isolated membrane material does not represent the intact in vivo organization of the mitotic ER.

Cell-free nuclear assembly assays have allowed us to separate NE formation into discrete steps: (1) targeting of NE precursor membranes to the chromatin surface (Newport and Dunphy, 1992; Sheehan et al., 1988; Vigers and Lohka, 1991); (2) fusion of NE membranes to form a tubular network on the chromatin surface (Hetzer et al., 2001); (3) formation of a closed INM and ONM, which is accompanied by the assembly of NPCs (Hetzer et al., 2000). The idea of vesicle fusion as the principal mechanism of NE formation in vitro is derived from findings that GTPS blocks NE formation, producing unfused vesicles that cover the surface of chromatin (Boman et al., 1992; Hetzer et al., 2001). NE formation on chromatin specifically requires Ran (Hetzer et al., 2000; Zhang and Clarke, 2000), and the following model has been proposed to account for its role. The Ran exchange factor RCC1 (Ohtsubo et al., 1989) is stably associated with chromatin, generating high levels of RanGTP around chromatin (Bilbao-Cortes et al., 2002; Hetzer et al., 2002; Hutchins et al., 2004). This triggers the release of the nuclear transport receptor importin β (Harel et al., 2003; Harel and Forbes, 2004; Nachury et al., 2001) from importin-β-binding proteins such as nucleoporins and thereby leads to NPC assembly (Harel et al., 2003; Walther et al., 2003). It could similarly be required for NE assembly. Targets of importin β that could be required for NE formation remain unknown; however, recent findings suggest that these are not membrane bound (see below). Additionally, Ran has been shown to be required for NE formation in C. elegans (Askjaer et al., 2002) and yeast (Ryan et al., 2003), but the cellular targets have not yet been identified.

NE formation is also sensitive to ATPS (Dreier and Rapoport, 2000; Hetzer et al., 2001) and antibodies against the AAA-ATPase p97 (Baur et al., 2007), a protein that has been implicated in homotypic membrane fusion (Roy et al., 2000) and ER retro-translocation (Ye et al., 2003). In addition, the SNARE-sequestering protein a-SNAP can block nuclear assembly (Baur et al., 2007; Hetzer et al., 2001). However, GTP hydrolysis, p97 and a-SNAP are also involved in the reconstitution of the ER network, prompting the alternative hypothesis that an intact ER network is required for nuclear assembly but no NE-specific fusion machinery is needed.

View larger version (76K): [in this window] [in a new window]   Fig. 2. The morphology of the starting membranes dictates the biochemical requirements of cell-free nuclear assembly. Classically, nuclei were formed by mixing membrane fragments with sperm chromatin and cytosol (classical nuclear assembly). In this case, membrane fragments bind to the chromatin surface, fuse into a tubular network and expand to form the NE. Alternatively, when ER fragments are preformed into an ER network prior to chromatin addition, the network binds to chromatin and expands to enclose the chromatin. The addition of homotypic ER fusion inhibitors blocks nuclear assembly when fragmented membranes are mixed with chromatin (classical nuclear assembly). However, when these inhibitors are added after ER network assembly, there is no affect on NE formation.

	Targeting membranes to chromatin during NE formation

Top Summary Introduction Tearing apart the nuclear... Reconstitution of the NE... Targeting membranes to chromatin... Membrane reshaping from tubule... Nuclear closure and expansion Perspectives References

 
If NE components reside in the mitotic ER, NE formation must be triggered by the binding of ER to chromatin. Recent work shows that tubule ends in the mitotic ER first targets chromatin both in vitro and in vivo (Fig. 1, anaphase) (Anderson and Hetzer, 2007). This could be more energetically favorable than ER tubules binding laterally along chromatin. Alternatively, NETs that target the ER to chromatin may preferentially localize to areas of high membrane curvature. Along the lateral surface of the tubule there is only significant membrane curvature in one axis, whereas at the end of a tubule membrane curvature is high along two axes.

The proteins that target membranes to chromatin are unknown; however, several NETs have been shown to bind to chromatin. LBR and Lap2B, lamin-associated NETs, bind to chromatin in vitro (Collas et al., 1996; Pyrpasopoulou et al., 1996), but their specific molecular targets remain unclear. Recently, LBR along with three other NETs, was shown to bind directly to DNA in vitro (Ulbert et al., 2006). NETs may thus target ER membranes to chromatin by binding to DNA at the onset of NE formation. Approximately 50% of >70 NETs identified have predicted cytosolic domains that have high pI values, which is indicative of DNA binding (Ulbert et al., 2006). NETs could therefore have redundant roles in membrane targeting during NE formation. Several candidates that may play a central role in membrane recruitment have been characterized. For example, when Ndc1, a transmembrane nucleoporin, is depleted from membranes, in vitro recruitment to chromatin is reduced (Mansfeld et al., 2006). Similarly, the depletion of LBR blocks membrane binding to chromatin (Pyrpasopoulou et al., 1996). Moreover, depletion of Sun1, a lamin-associated NET that targets the initial ER-chromatin contact point in vivo, delays nuclear formation (Chi et al., 2007). It will be interesting to test the roles these proteins play in NE formation and determine what other NETs are also involved.

	Membrane reshaping from tubule tip to flat sheet

Top Summary Introduction Tearing apart the nuclear... Reconstitution of the NE... Targeting membranes to chromatin... Membrane reshaping from tubule... Nuclear closure and expansion Perspectives References

 
After the immobilization of ER tubules around chromatin, the next step in NE formation is the massive flattening of the tubular network into membrane sheets (Anderson and Hetzer, 2007). This reshaping event is at least in part mediated by the direct binding of membrane proteins to chromatin, because flat membrane sheets form from an ER network on DNA in the absence of cytosol (Anderson and Hetzer, 2007).

Further support for a direct role of DNA-membrane protein interactions comes from the findings that the formation of flat membrane sheets in vitro is less efficient on chromatin than on protein-free DNA (Anderson and Hetzer, 2007). Since access to naked DNA in chromatin is known to be regulated, NE formation in vivo might involve active remodeling of chromatin. Sperm chromatin must first be decondensed with cytosol and GTP before nuclei assemble in the presence of GTPS, which suggests that a GTPase is involved in chromatin reorganization and may be required for NET recruitment. One candidate of course is Ran.

View larger version (50K): [in this window] [in a new window]   Fig. 3. Hole closure is the final step for sealing of the nuclei. (A) After the ER network collapses onto the chromatin surface (left panel), membrane tubules flatten and merge into sheets (center panel). Connections between the INM and ONM in the form of small holes are the result of membrane flattening and merging (right panel). (B) There are three possible mechanisms for closure of the final connecting points between the INM and ONM. Protein-mediated constriction of the membrane hole may lead to fission of the two membrane sheets (`annular fusion'). This step may also be mediated by progressive tethering of the INM to chromatin by DNA-binding NETs (INM tethering). Alternatively, the final holes of NE formation may act as sites of NPC assembly (NPC assembly).

Finally, although flat membrane sheets form in vitro in the absence of cytosol, cytosolic factors might nevertheless play a role in vivo. Furthermore, if interactions between proteins involved in NE formation and DNA indeed occur in vivo, it will be interesting to see whether these binding sites are maintained in interphase and help organize chromatin.

	Nuclear closure and expansion

Top Summary Introduction Tearing apart the nuclear... Reconstitution of the NE... Targeting membranes to chromatin... Membrane reshaping from tubule... Nuclear closure and expansion Perspectives References

 
When membrane sheets merge during NE formation, small holes, the last connections between the INM and ONM, remain (Fig. 3A). It is possible that annular fusion (Burke and Ellenberg, 2002) is required to close these remaining remnants of the tubular network. Nuclei can seal in the presence of GTPS and ATPS (Anderson and Hetzer, 2007), which suggests that energy is not required for the final annular fusion step. In the absence of biophysical characterization of membrane-chromatin interactions at this step, we can only speculate on how hole closure occurs. It could be mediated by a luminal fission machinery (Burke, 2001) that does not require the hydrolysis of ATP or GTP, or close spontaneously as a consequence of the pulling force on the INM due to accumulating DNA-or chromatin-binding proteins (Fig. 3B). An alternative scenario is that these holes are targeted to sites of NPC assembly. In this scenario, membrane-bound nucleoporins are simply recruited to the points of fusion between the INM and ONM, targeting these holes to assembling subcomplexes on the chromatin surface. Membrane-associated nucleoporin targeting could be due to the unique membrane curvature at these small holes, where there is a convex surface across the INM and ONM and concave surface between the two membranes (Antonin and Mattaj, 2005). The fate of the remaining holes in the forming NE will be an interesting future area of study.

After nuclei are fully enclosed, the NE surface area increases during interphase (Maul et al., 1972). Nuclear expansion requires the supply of additional nuclear membrane components. Recently, nuclear expansion was recapitulated in vitro by the addition of membranes and cytosol to assembled nuclei (D'Angelo et al., 2006). Nuclear growth can be blocked by physically disrupting the connection between nuclei and the peripheral ER, which suggests that membranes feed into the ONM via connections with ER tubules (Anderson and Hetzer, 2007). Growth of the INM would then require passage of membrane components through the points of fusion with the ONM and the NPCs. Since nuclei of the same cell types in a given tissue are similar in size, it remains unclear how their final size of nuclei is regulated.

	Perspectives

Top Summary Introduction Tearing apart the nuclear... Reconstitution of the NE... Targeting membranes to chromatin... Membrane reshaping from tubule... Nuclear closure and expansion Perspectives References

 
NE formation is a vital membrane-restructuring event that appears tightly linked to the dynamic behavior of the ER network. Many open questions about the molecular mechanisms of tethering of ER tubules to chromatin and how flat sheets form remain. What is the precise role of DNA-binding ER proteins in the different steps of NE formation? Are ER luminal proteins involved in tubule flattening or is there a mechanism that removes `membrane-curving' proteins such as reticulons? It will also be interesting to analyze the DNA-binding properties of NE proteins in vivo to determine whether they help establish chromatin organization at the nuclear periphery. Further studies of the structural aspects of membrane remodeling at the forming nucleus may have implications for the maintenance and dynamic morphology of other organelles. Proteins that occupy unique membrane domains, such as reticulons, probably play a major role defining the overall architecture and function of eukaryotic cells. Lastly, the size regulation of organelles such as the nucleus remains a mystery, which when deciphered may provide new insights into cell differentiation and development.

	References

Top Summary Introduction Tearing apart the nuclear... Reconstitution of the NE... Targeting membranes to chromatin... Membrane reshaping from tubule... Nuclear closure and expansion Perspectives References

 

Akhtar, A. and Gasser, S. M. (2007). The nuclear envelope and transcriptional control. Nat. Rev. Genet. 8, 507-517.[CrossRef][Medline]

Anderson, D. J. and Hetzer, M. W. (2007). Nuclear envelope formation by chromatin-mediated reorganization of the endoplasmic reticulum. Nat. Cell Biol. 9, 1160-1166.[CrossRef][Medline]

Antonin, W. and Mattaj, I. W. (2005). Nuclear pore complexes: round the bend? Nat. Cell Biol. 7, 10-12.[CrossRef][Medline]

Apel, E. D., Lewis, R. M., Grady, R. M. and Sanes, J. R. (2000). Syne-1, a dystrophin- and Klarsicht-related protein associated with synaptic nuclei at the neuromuscular junction. J. Biol. Chem. 275, 31986-31995.[Abstract/Free Full Text]

Askjaer, P., Galy, V., Hannak, E. and Mattaj, I. W. (2002). Ran GTPase cycle and importins alpha and beta are essential for spindle formation and nuclear envelope assembly in living Caenorhabditis elegans embryos. Mol. Biol. Cell 13, 4355-4370.[Abstract/Free Full Text]

Baur, T., Ramadan, K., Schlundt, A., Kartenbeck, J. and Meyer, H. H. (2007). NSF- and SNARE-mediated membrane fusion is required for nuclear envelope formation and completion of nuclear pore complex assembly in Xenopus laevis egg extracts. J. Cell Sci. 120, 2895-2903.[Abstract/Free Full Text]

Beaudouin, J., Gerlich, D., Daigle, N., Eils, R. and Ellenberg, J. (2002). Nuclear envelope breakdown proceeds by microtubule-induced tearing of the lamina. Cell 108, 83-96.[CrossRef][Medline]

Bilbao-Cortes, D., Hetzer, M., Langst, G., Becker, P. B. and Mattaj, I. W. (2002). Ran binds to chromatin by two distinct mechanisms. Curr. Biol. 12, 1151-1156.[CrossRef][Medline]

Boman, A. L., Delannoy, M. R. and Wilson, K. L. (1992). GTP hydrolysis is required for vesicle fusion during nuclear envelope assembly in vitro. J. Cell Biol. 116, 281-294.[Abstract/Free Full Text]

Burke, B. (2001). The nuclear envelope: filling in gaps. Nat. Cell Biol. 3, E273-E274.[CrossRef][Medline]

Burke, B. and Ellenberg, J. (2002). Remodelling the walls of the nucleus. Nat. Rev. Mol. Cell Biol. 3, 487-497.[CrossRef][Medline]

Burke, B. and Stewart, C. L. (2002). Life at the edge: the nuclear envelope and human disease. Nat. Rev. Mol. Cell Biol. 3, 575-585.[CrossRef][Medline]

Callan, H. G. and Tomlin, S. G. (1950). Experimental studies on amphibian oocyte nuclei. I. Investigation of the structure of the nuclear membrane by means of the electron microscope. Proc. R. Soc. Lond. B Biol. Sci. 137, 367-378.[Medline]

Chi, Y. H., Haller, K., Peloponese, J. M., Jr and Jeang, K. T. (2007). Histone acetyltransferase hALP and nuclear membrane protein hsSUN1 function in decondensation of mitotic chromosomes. J. Biol. Chem. 282, 27447-27458.[Abstract/Free Full Text]

Cohen, M., Tzur, Y. B., Neufeld, E., Feinstein, N., Delannoy, M. R., Wilson, K. L. and Gruenbaum, Y. (2002). Transmission electron microscope studies of the nuclear envelope in Caenorhabditis elegans embryos. J. Struct. Biol. 140, 232-240.[CrossRef][Medline]

Collas, I. and Courvalin, J. C. (2000). Sorting nuclear membrane proteins at mitosis. Trends Cell Biol. 10, 5-8.[CrossRef][Medline]

Collas, P., Courvalin, J. C. and Poccia, D. (1996). Targeting of membranes to sea urchin sperm chromatin is mediated by a lamin B receptor-like integral membrane protein. J. Cell Biol. 135, 1715-1725.[Abstract/Free Full Text]

Cotter, L., Allen, T. D., Kiseleva, E. and Goldberg, M. W. (2007). Nuclear membrane disassembly and rupture. J. Mol. Biol. 369, 683-695.[CrossRef][Medline]

Daigle, N., Beaudouin, J., Hartnell, L., Imreh, G., Hallberg, E., Lippincott-Schwartz, J. and Ellenberg, J. (2001). Nuclear pore complexes form immobile networks and have a very low turnover in live mammalian cells. J. Cell Biol. 154, 71-84.[Abstract/Free Full Text]

D'Angelo, M. A. and Hetzer, M. W. (2006). The role of the nuclear envelope in cellular organization. Cell. Mol. Life Sci. 63, 316-332.[CrossRef][Medline]

D'Angelo, M. A., Anderson, D. J., Richard, E. and Hetzer, M. W. (2006). Nuclear pores form de novo from both sides of the nuclear envelope. Science 312, 440-443.[Abstract/Free Full Text]

Dasso, M. (2002). The Ran GTPase: theme and variations. Curr. Biol. 12, R502-R508.[CrossRef][Medline]

De Souza, C. P., Osmani, A. H., Hashmi, S. B. and Osmani, S. A. (2004). Partial nuclear pore complex disassembly during closed mitosis in Aspergillus nidulans. Curr. Biol. 14, 1973-1984.[CrossRef][Medline]

Di Fiore, B., Ciciarello, M. and Lavia, P. (2004). Mitotic functions of the Ran GTPase network: the importance of being in the right place at the right time. Cell Cycle 3, 305-313.[Medline]

Dreier, L. and Rapoport, T. A. (2000). In vitro formation of the endoplasmic reticulum occurs independently of microtubules by a controlled fusion reaction. J. Cell Biol. 148, 883-898.[Abstract/Free Full Text]

Drummond, S., Ferrigno, P., Lyon, C., Murphy, J., Goldberg, M., Allen, T., Smythe, C. and Hutchison, C. J. (1999). Temporal differences in the appearance of NEP-B78 and an LBR-like protein during Xenopus nuclear envelope reassembly reflect the ordered recruitment of functionally discrete vesicle types. J. Cell Biol. 144, 225-240.[Abstract/Free Full Text]

Ellenberg, J., Siggia, E. D., Moreira, J. E., Smith, C. L., Presley, J. F., Worman, H. J. and Lippincott-Schwartz, J. (1997). Nuclear membrane dynamics and reassembly in living cells: targeting of an inner nuclear membrane protein in interphase and mitosis. J. Cell Biol. 138, 1193-1206.[Abstract/Free Full Text]

Fahrenkrog, B., Koser, J. and Aebi, U. (2004). The nuclear pore complex: a jack of all trades? Trends Biochem. Sci. 29, 175-182.[CrossRef][Medline]

Foisner, R. (2001). Inner nuclear membrane proteins and the nuclear lamina. J. Cell Sci. 114, 3791-3792.[Free Full Text]

Foisner, R. (2003). Cell cycle dynamics of the nuclear envelope. Scientific World Journal 3, 1-20.[Medline]

Forbes, D. J., Kirschner, M. W. and Newport, J. W. (1983). Spontaneous formation of nucleus-like structures around bacteriophage DNA microinjected into Xenopus eggs. Cell 34, 13-23.[CrossRef][Medline]

Gant, T. M. and Wilson, K. L. (1997). Nuclear assembly. Annu. Rev. Cell Dev. Biol. 13, 669-695.[CrossRef][Medline]

Gerace, L. and Blobel, G. (1980). The nuclear envelope lamina is reversibly depolymerized during mitosis. Cell 19, 277-287.[CrossRef][Medline]

Gerace, L. and Burke, B. (1988). Functional organization of the nuclear envelope. Annu. Rev. Cell Biol. 4, 335-374.[CrossRef][Medline]

Gruenbaum, Y., Goldman, R. D., Meyuhas, R., Mills, E., Margalit, A., Fridkin, A., Dayani, Y., Prokocimer, M. and Enosh, A. (2003). The nuclear lamina and its functions in the nucleus. Int. Rev. Cytol. 226, 1-62.[Medline]

Gruenbaum, Y., Margalit, A., Goldman, R. D., Shumaker, D. K. and Wilson, K. L. (2005). The nuclear lamina comes of age. Nat. Rev. Mol. Cell Biol. 6, 21-31.[CrossRef][Medline]

Harel, A. and Forbes, D. J. (2004). Importin beta: conducting a much larger cellular symphony. Mol. Cell 16, 319-330.[Medline]

Harel, A., Chan, R. C., Lachish-Zalait, A., Zimmerman, E., Elbaum, M. and Forbes, D. J. (2003). Importin beta negatively regulates nuclear membrane fusion and nuclear pore complex assembly. Mol. Biol. Cell 14, 4387-4396.[Abstract/Free Full Text]

Heald, R., Tournebize, R., Blank, T., Sandaltzopoulos, R., Becker, P., Hyman, A. and Karsenti, E. (1996). Self-organization of microtubules into bipolar spindles around artificial chromosomes in Xenopus egg extracts. Nature 382, 420-425.[CrossRef][Medline]

Heath, B. (1980). Variant mitoses in lower eukaryotes:indicators of evolution of mitosis? Int. Rev. Cytol. 64, 1-80.[CrossRef]

Hetzer, M., Bilbao-Cortes, D., Walther, T. C., Gruss, O. J. and Mattaj, I. W. (2000). GTP hydrolysis by Ran is required for nuclear envelope assembly. Mol. Cell 5, 1013-1024.[CrossRef][Medline]

Hetzer, M., Meyer, H. H., Walther, T. C., Bilbao-Cortes, D., Warren, G. and Mattaj, I. W. (2001). Distinct AAA-ATPase p97 complexes function in discrete steps of nuclear assembly. Nat. Cell Biol. 3, 1086-1091.[CrossRef][Medline]

Hetzer, M., Gruss, O. J. and Mattaj, I. W. (2002). The Ran GTPase as a marker of chromosome position in spindle formation and nuclear envelope assembly. Nat. Cell Biol. 4, E177-E184.[CrossRef][Medline]

Hetzer, M., Walther, T. C. and Mattaj, I. W. (2005). Pushing the envelope: structure, function, and dynamics of the nuclear periphery. Annu. Rev. Cell Dev. Biol. 21, 347-380.[CrossRef][Medline]

Holmer, L. and Worman, H. J. (2001). Inner nuclear membrane proteins: functions and targeting. Cell. Mol. Life Sci. 58, 1741-1747.[CrossRef][Medline]

Hutchins, J. R., Moore, W. J., Hood, F. E., Wilson, J. S., Andrews, P. D., Swedlow, J. R. and Clarke, P. R. (2004). Phosphorylation regulates the dynamic interaction of RCC1 with chromosomes during mitosis. Curr. Biol. 14, 1099-1104.[CrossRef][Medline]

Hutchison, C. J. (2002). Lamins: building blocks or regulators of gene expression? Nat. Rev. Mol. Cell Biol. 3, 848-858.[CrossRef][Medline]

Joseph, J. (2006). Ran at a glance. J. Cell Sci. 119, 3481-3484.[Free Full Text]

Lenart, P. and Ellenberg, J. (2003). Nuclear envelope dynamics in oocytes: from germinal vesicle breakdown to mitosis. Curr. Opin. Cell Biol. 15, 88-95.[CrossRef][Medline]

Lenart, P., Rabut, G., Daigle, N., Hand, A. R., Terasaki, M. and Ellenberg, J. (2003). Nuclear envelope breakdown in starfish oocytes proceeds by partial NPC disassembly followed by a rapidly spreading fenestration of nuclear membranes. J. Cell Biol. 160, 1055-1068.[Abstract/Free Full Text]

Liu, J., Prunuske, A. J., Fager, A. M. and Ullman, K. S. (2003). The COPI complex functions in nuclear envelope breakdown and is recruited by the nucleoporin Nup153. Dev. Cell 5, 487-498.[CrossRef][Medline]

Lohka, M. J. and Masui, Y. (1983). Formation in vitro of sperm pronuclei and mitotic chromosomes induced by amphibian ooplasmic components. Science 220, 719-721.[Abstract/Free Full Text]

Lusk, C. P., Blobel, G. and King, M. C. (2007). Highway to the inner nuclear membrane: rules for the road. Nat. Rev. Mol. Cell Biol. 8, 414-420.[CrossRef][Medline]

Mansfeld, J., Guttinger, S., Hawryluk-Gara, L. A., Pante, N., Mall, M., Galy, V., Haselmann, U., Muhlhausser, P., Wozniak, R. W., Mattaj, I. W. et al. (2006). The conserved transmembrane nucleoporin NDC1 is required for nuclear pore complex assembly in vertebrate cells. Mol. Cell 22, 93-103.[CrossRef][Medline]

Maul, G. G., Maul, H. M., Scogna, J. E., Lieberman, M. W., Stein, G. S., Hsu, B. Y. and Borun, T. W. (1972). Time sequence of nuclear pore formation in phytohemagglutinin-stimulated lymphocytes and in HeLa cells during the cell cycle. J. Cell Biol. 55, 433-447.[Abstract/Free Full Text]

Mislow, J. M., Holaska, J. M., Kim, M. S., Lee, K. K., Segura-Totten, M., Wilson, K. L. and McNally, E. M. (2002). Nesprin-1alpha self-associates and binds directly to emerin and lamin A in vitro. FEBS Lett. 525, 135-140.[CrossRef][Medline]

Mounkes, L. C. and Stewart, C. L. (2004). Aging and nuclear organization: lamins and progeria. Curr. Opin. Cell Biol. 16, 322-327.[CrossRef][Medline]

Mounkes, L., Kozlov, S., Burke, B. and Stewart, C. L. (2003). The laminopathies: nuclear structure meets disease. Curr. Opin. Genet. Dev. 13, 223-230.[CrossRef][Medline]

Muchir, A. and Worman, H. J. (2004). The nuclear envelope and human disease. Physiology Bethesda 19, 309-314.[CrossRef][Medline]

Muhlhausser, P. and Kutay, U. (2007). An in vitro nuclear disassembly system reveals a role for the RanGTPase system and microtubule-dependent steps in nuclear envelope breakdown. J. Cell Biol. 178, 595-610.[Abstract/Free Full Text]

Nachury, M. V., Maresca, T. J., Salmon, W. C., Waterman-Storer, C. M., Heald, R. and Weis, K. (2001). Importin beta is a mitotic target of the small GTPase Ran in spindle assembly. Cell 104, 95-106.[CrossRef][Medline]

Nagano, A. and Arahata, K. (2000). Nuclear envelope proteins and associated diseases. Curr. Opin. Neurol. 13, 533-539.[CrossRef][Medline]

Newport, J. (1987). Nuclear reconstitution in vitro: stages of assembly around protein-free DNA. Cell 48, 205-217.[CrossRef][Medline]

Newport, J. W. and Forbes, D. J. (1987). The nucleus: structure, function, and dynamics. Annu. Rev. Biochem. 56, 535-565.[CrossRef][Medline]

Newport, J. and Spann, T. (1987). Disassembly of the nucleus in mitotic extracts: membrane vesicularization, lamin disassembly, and chromosome condensation are independent processes. Cell 48, 219-230.[CrossRef][Medline]

Newport, J. and Dunphy, W. (1992). Characterization of the membrane binding and fusion events during nuclear envelope assembly using purified components. J. Cell Biol. 116, 295-306.[Abstract/Free Full Text]

Nigg, E. A. (1992). Assembly-disassembly of the nuclear lamina. Curr. Opin. Cell Biol. 4, 105-109.[CrossRef][Medline]

Ohtsubo, M., Okazaki, H. and Nishimoto, T. (1989). The RCC1 protein, a regulator for the onset of chromosome condensation locates in the nucleus and binds to DNA. J. Cell Biol. 109, 1389-1397.[Abstract/Free Full Text]

Pollex, R. L. and Hegele, R. A. (2004). Hutchinson-Gilford progeria syndrome. Clin. Genet. 66, 375-381.[CrossRef][Medline]

Pyrpasopoulou, A., Meier, J., Maison, C., Simos, G. and Georgatos, S. D. (1996). The lamin B receptor (LBR) provides essential chromatin docking sites at the nuclear envelope. EMBO J. 15, 7108-7119.[Medline]

Rabouille, C. and Klumperman, J. (2005). Opinion: the maturing role of COPI vesicles in intra-Golgi transport. Nat. Rev. Mol. Cell Biol. 6, 812-817.[Medline]

Robbins, E. and Gonatas, N. K. (1964). The ultrastructure of a mammalian cell during the mitotic cycle. J. Cell Biol. 21, 429-463.[Abstract/Free Full Text]

Roux, K. J. and Burke, B. (2007). Nuclear envelope defects in muscular dystrophy. Biochim. Biophys. Acta 1772, 118-127.[Medline]

Roy, L., Bergeron, J. J., Lavoie, C., Hendriks, R., Gushue, J., Fazel, A., Pelletier, A., Morre, D. J., Subramaniam, V. N., Hong, W. et al. (2000). Role of p97 and syntaxin 5 in the assembly of transitional endoplasmic reticulum. Mol. Biol. Cell 11, 2529-2542.[Abstract/Free Full Text]

Ryan, K. J., McCaffery, J. M. and Wente, S. R. (2003). The Ran GTPase cycle is required for yeast nuclear pore complex assembly. J. Cell Biol. 160, 1041-1053.[Abstract/Free Full Text]

Salina, D., Bodoor, K., Eckley, D. M., Schroer, T. A., Rattner, J. B. and Burke, B. (2002). Cytoplasmic dynein as a facilitator of nuclear envelope breakdown. Cell 108, 97-107.[CrossRef][Medline]

Sasagawa, S., Yamamoto, A., Ichimura, T., Omata, S. and Horigome, T. (1999). In vitro nuclear assembly with affinity-purified nuclear envelope precursor vesicle fractions, PV1 and PV2. Eur. J. Cell Biol. 78, 593-600.[Medline]

Sazer, S. (2005). Nuclear envelope: nuclear pore complexity. Curr. Biol. 15, R23-R26.[CrossRef][Medline]

Sazer, S. and Dasso, M. (2000). The ran decathlon: multiple roles of Ran. J. Cell Sci. 113, 1111-1118.[Abstract]

Schirmer, E. C., Florens, L., Guan, T., Yates, J. R., 3rd and Gerace, L. (2003). Nuclear membrane proteins with potential disease links found by subtractive proteomics. Science 301, 1380-1382.[Abstract/Free Full Text]

Shaklai, S., Amariglio, N., Rechavi, G. and Simon, A. J. (2007). Gene silencing at the nuclear periphery. FEBS J. 274, 1383-1392.[CrossRef][Medline]

Sheehan, M. A., Mills, A. D., Sleeman, A. M., Laskey, R. A. and Blow, J. J. (1988). Steps in the assembly of replication-competent nuclei in a cell-free system from Xenopus eggs. J. Cell Biol. 106, 1-12.[Abstract/Free Full Text]

Shibata, Y., Voeltz, G. K. and Rapoport, T. A. (2006). Rough sheets and smooth tubules. Cell 126, 435-439.[CrossRef][Medline]

Stavru, F., Hulsmann, B. B., Spang, A., Hartmann, E., Cordes, V. C. and Gorlich, D. (2006). NDC1: a crucial membrane-integral nucleoporin of metazoan nuclear pore complexes. J. Cell Biol. 173, 509-519.[Abstract/Free Full Text]

Taddei, A. (2007). Active genes at the nuclear pore complex. Curr. Opin. Cell Biol. 19, 305-310.[CrossRef][Medline]

Taddei, A., Hediger, F., Neumann, F. R. and Gasser, S. M. (2004). The function of nuclear architecture: a genetic approach. Annu. Rev. Genet. 38, 305-345.[CrossRef][Medline]

Tzur, Y. B., Wilson, K. L. and Gruenbaum, Y. (2006). SUN-domain proteins: `Velcro' that links the nucleoskeleton to the cytoskeleton. Nat. Rev. Mol. Cell Biol. 7, 782-788.[CrossRef][Medline]

Ulbert, S., Platani, M., Boue, S. and Mattaj, I. W. (2006). Direct membrane protein-DNA interactions required early in nuclear envelope assembly. J. Cell Biol. 173, 469-476.[Abstract/Free Full Text]

Ulitzur, N., Harel, A., Goldberg, M., Feinstein, N. and Gruenbaum, Y. (1997). Nuclear membrane vesicle targeting to chromatin in a Drosophila embryo cell-free system. Mol. Biol. Cell 8, 1439-1448.[Abstract]

Vasu, S. K. and Forbes, D. J. (2001). Nuclear pores and nuclear assembly. Curr. Opin. Cell Biol. 13, 363-375.[CrossRef][Medline]

Vigers, G. P. and Lohka, M. J. (1991). A distinct vesicle population targets membranes and pore complexes to the nuclear envelope in Xenopus eggs. J. Cell Biol. 112, 545-556.[Abstract/Free Full Text]

Voeltz, G. K., Rolls, M. M. and Rapoport, T. A. (2002). Structural organization of the endoplasmic reticulum. EMBO Rep. 3, 944-950.[CrossRef][Medline]

Voeltz, G. K., Prinz, W. A., Shibata, Y., Rist, J. M. and Rapoport, T. A. (2006). A class of membrane proteins shaping the tubular endoplasmic reticulum. Cell 124, 573-586.[CrossRef][Medline]

Walther, T. C., Askjaer, P., Gentzel, M., Habermann, A., Griffiths, G., Wilm, M., Mattaj, I. W. and Hetzer, M. (2003). RanGTP mediates nuclear pore complex assembly. Nature 424, 689-694.[CrossRef][Medline]

Wente, S. R. (2000). Gatekeepers of the nucleus. Science 288, 1374-1377.[Abstract/Free Full Text]

Wiese, C., Goldberg, M. W., Allen, T. D. and Wilson, K. L. (1997). Nuclear envelope assembly in Xenopus extracts visualized by scanning EM reveals a transport-dependent `envelope smoothing' event. J. Cell Sci. 110, 1489-1502.[Abstract]

Wilhelmsen, K., Ketema, M., Truong, H. and Sonnenberg, A. (2006). KASH-domain proteins in nuclear migration, anchorage and other processes. J. Cell Sci. 119, 5021-5029.[Abstract/Free Full Text]

Wilson, K. L. (2000). The nuclear envelope, muscular dystrophy and gene expression. Trends Cell Biol. 10, 125-129.[CrossRef][Medline]

Worman, H. J. and Courvalin, J. C. (2000). The inner nuclear membrane. J. Membr. Biol. 177, 1-11.[CrossRef][Medline]

Worman, H. J. and Courvalin, J. C. (2004). How do mutations in lamins A and C cause disease? J. Clin. Invest. 113, 349-351.[CrossRef][Medline]

Wozniak, R. W. and Lusk, C. P. (2003). Nuclear pore complexes. Curr. Biol. 13, R169.[CrossRef][Medline]

Yang, L., Guan, T. and Gerace, L. (1997). Integral membrane proteins of the nuclear envelope are dispersed throughout the endoplasmic reticulum during mitosis. J. Cell Biol. 137, 1199-1210.[Abstract/Free Full Text]

Ye, Y., Meyer, H. H. and Rapoport, T. A. (2003). Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains. J. Cell Biol. 162, 71-84.[Abstract/Free Full Text]

Zhang, C. and Clarke, P. R. (2000). Chromatin-independent nuclear envelope assembly induced by Ran GTPase in Xenopus egg extracts. Science 288, 1429-1432.[Abstract/Free Full Text]

Zhang, Q., Skepper, J. N., Yang, F., Davies, J. D., Hegyi, L., Roberts, R. G., Weissberg, P. L., Ellis, J. A. and Shanahan, C. M. (2001). Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues. J. Cell Sci. 114, 4485-4498.[Medline]

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