The nucleoplasmic reticulum: form and function

doi:10.1016/j.tcb.2011.03.008

Trends in Cell Biology

Volume 21, Issue 6, June 2011, Pages 362-373

https://doi.org/10.1016/j.tcb.2011.03.008 Get rights and content

The nuclear envelope (NE) physically separates nucleoplasm and cytoplasm, contributes to nuclear structural integrity, controls selective bidirectional transport of ions and macromolecular cargo, regulates gene expression, and acts as a mechanotransducer and a platform for signalling. It is noteworthy however that the NE is not simply a smooth-surfaced outer boundary but is interrupted by invaginations that reach deep within the nucleoplasm and could even traverse the nucleus completely. The existence of such a complex branched network of invaginations forming a nucleoplasmic reticulum (NR) provides sites that are capable of carrying out the ‘conventional’ NE functions deep within the nucleus in regions that would otherwise be remote from the nuclear periphery. In this review, we describe the structural features of NR in normal and pathological states and discuss the current understanding of their functional and possible pathological roles.

Section snippets

The nuclear envelope

The nuclear boundary or nuclear envelope (NE) is a unique structure comprising two phospholipid bilayers [the inner nuclear membrane (INM) and outer nuclear membrane (ONM)], an intermembrane space (IMS), and a meshwork or lamina rich in intermediate filament proteins which underlies the INM [1]. The NE is pierced at intervals by nuclear pores, highly structured focal continuities between the two membranes. The NE is not merely a fence between nucleoplasm and cytoplasm; it also contributes to

NR structure

NR invaginations fall into two main classes depending on whether the ONM is involved (we offer a classification as type I and type II; Box 1). Type I invaginations are those where the INM invaginates into the nucleoplasm, whereas type II involve the invagination of both the outer and inner nuclear membranes. Although an NR invagination can occur alone, some nuclei contain multiple invaginations and the two classes could coexist in the same nucleus (Figure 1). Indeed, the original serial section

Composition

The membranes of the NR resemble those of the NE. In type II invaginations the ONM resembles ER (e.g. contains Sec61p), the IMS contains the ER marker proteins disulphide isomerase and calreticulin and also high mannose N-linked oligosaccharides [detected by the lectin concanavalin A (ConA)] [5] and the inner membrane contains characteristic INM proteins (emerin [24], lamin B receptor [25], and LAP2beta). The composition of type I NR could be more restricted, with reports that it might be

Regulation

NR could arise during NE reassembly after mitosis if synchrony between chromosome decondensation and fusion of recruited NE fragments is imperfect and chromatin-bound ER/NE cisternae thereby become trapped in interstitial spaces, a process observed in tobacco cells [34]. However, NR can be formed de novo without mitosis [11], persists throughout interphase 5, 35 and shows heritable patterns in specific cell types [5], strongly implying physiological regulation.

During cellularisation in

Function

The functions of NR networks remain speculative, although there is mounting evidence for a role in calcium signalling. Preliminary evidence suggests additional roles in gene expression, transport, and nuclear lipid metabolism.

The existence of NR continuous with ER offers a potential deep nuclear calcium-signalling source 19, 65. Calcium signalling is involved in many processes, including proliferation and apoptosis. It is thought that one of the factors determining the outcome of such

Pathological significance of NR

It might be argued that an NR is an artifact caused by additional strain on the NE when cells are grown in 2D culture, providing structural support for the nucleus under compression but having no other functional role. However, the widespread observation of NR in nuclei from tissues 5, 28, 33 and cells grown in 3D cell culture [83] confirms that the NR is a naturally occurring structure and not a side-effect of the culture environment.

As part of the Bloom–Richardson grading system [84], nuclear

Conclusion and future perspectives

In this short survey we hope to have convinced readers of the existence and potential importance of a nucleoplasmic reticulum. The presence of regulated intranuclear membrane structures, both tubular and vesicular, could hold the key to explaining initially confusing observations on virus entry and exit and on focal intranuclear calcium signals.

Several further roles for the NR have been hinted at by preliminary observations and offer new areas for exploration. For example, nucleoli often

Acknowledgements

Relevant work in the laboratory of the authors has been supported by the Medical Research Council, the Rhodes Trust, the E.P. Abrahams Trust, and by Tim and Kit Kemp. We would like to apologise to all those whose contributions in this area have been referred to only indirectly in reviews because of lack of bibliographic space.

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The nuclear envelope (NE) is a critical component in maintaining the function and structure of the eukaryotic nucleus. The NE and lamina are disassembled during each cell cycle to enable an open mitosis. Nuclear architecture construction and deconstruction is a prime example of a circular economy, as it fulfills a highly efficient recycling program bound to continuous assessment of the quality and functionality of the building blocks. Alterations in the nuclear dynamics and lamina structure have emerged as important contributors to both oncogenic transformation and cancer progression. However, the knowledge of the NE breakdown and reassembly is still limited to a fraction of participating proteins and complexes. As cancer cells contain highly diverse nuclei in terms of DNA content, but also in terms of nuclear number, size, and shape, it is of great interest to understand the intricate relationship between these nuclear features in cancer cell pathophysiology. In this review, we provide insights into how those NE dynamics are regulated, and how lamina destabilization processes may alter the NE circular economy. Moreover, we expand the knowledge of the lamina-associated domain region by using strategic algorithms, including Artificial Intelligence, to infer protein associations, assess their function and location, and predict cancer-type specificity with implications for the future of cancer diagnosis, prognosis and treatment. Using this approach we identified NUP98 and MECP2 as potential proteins that exhibit upregulation in Acute Myeloid Leukemia (LAML) patients with implications for early diagnosis.
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^*: These authors contributed equally to this work.

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Trends in Cell Biology

ReviewThe nucleoplasmic reticulum: form and function

Section snippets

The nuclear envelope

NR structure

Composition

Regulation

Function

Pathological significance of NR

Conclusion and future perspectives

Acknowledgements

Curr. Opin. Cell Biol.

J. Ultrastruct. Res.

Trends Cell Biol.

Biophys. J.

Am. J. Pathol.

Tissue Cell

Exp. Cell Res.

Biochem. Biophys. Res. Commun.

Curr. Opin. Cell Biol.

J. Biol. Chem.

Differentiation

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Plant Physiol. Biochem.

Curr. Biol.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Eur. J. Cell Biol.

J. Biol. Chem.

Biochim. Biophys. Acta

Cell

J. Biol. Chem.

Biophys. J.

Cell Calcium

Biochim. Biophys. Acta

Cell Calcium

Cell Calcium

Cell Calcium

Three-dimensional analysis of given cell structures: nucleolus, nucleoskeleton and nuclear inclusions

Methods Achiev. Exp. Pathol.

Nuclear membrane modifications in polytene nuclei of Drosophila melanogaster: serial reconstruction and cytochemistry

Anat. Rec.

Interphase nuclei of many mammalian cell types contain deep, dynamic, tubular membrane-bound invaginations of the nuclear envelope

J. Cell Biol.

Subdiffraction multicolor imaging of the nuclear periphery with 3D structured illumination microscopy

Science

Three-dimensional cellular ultrastructure resolved by X-ray microscopy

Nat. Methods

Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum

Nat. Cell Biol.

Astrocyte elevated gene-1: far more than just a gene regulated in astrocytes

Cancer Res.

Nuclear assembly

Annu. Rev. Cell Dev. Biol.

Major binding sites for the nuclear import receptor are the internal nucleoporin Nup153 and the adjacent nuclear filament protein Tpr

J. Cell Biol.

The comparative analysis of subcellular fractionation methods for revealing of alpha-actinin 1 and alpha-actinin 4 in A431 cells [article in Russian]

Tsitologiia

Nuclear mitochondria?

Science

Nuclear lamins: laminopathies and their role in premature ageing

Physiol. Rev.

Nuclear membrane dynamics and reassembly in living cells: targeting of an inner nuclear membrane protein in interphase and mitosis

J. Cell Biol.

The lamin CxxM motif promotes nuclear membrane growth

J. Cell Sci.

Dynamics of the nuclear lamina as monitored by GFP-tagged A-type lamins

J. Cell Sci.

Alpha smooth muscle actin distribution in cytoplasm and nuclear invaginations of connective tissue fibroblasts

Histochem. Cell Biol.

Cellular mechanotransduction: putting all the pieces together again

FASEB J.

Coupling of the nucleus and cytoplasm: role of the LINC complex

J. Cell Biol.

Tissue stretch induces nuclear remodeling in connective tissue fibroblasts

Histochem. Cell Biol.

Nuclear envelope-limited chromatin sheets (ELCS) and heterochromatin higher order structure

Chromosoma

Review
The nucleoplasmic reticulum: form and function