The Nuclear Envelope

Current projects

• Understanding the mechanism of fat-loss in partial lipodystrophy, in particular focusing on the potential role of lamin A interaction with the adipocyte differentiation factor, SREBP1.
• Understanding the role of ZMPSTE24 and pre-lamin A processing in disease causation.
• Characterisation of the SUN domain family of proteins and their role in nuclear positioning and migration.

Our lab is interested in understanding nuclear envelope structure and function, in particular focusing on its involvement in a range of inherited disorders known as laminopathies.

The nuclear envelope (NE) is a double membrane structure that separates chromatin from the cytoplasm, thereby allowing temporal control of DNA replication and transcription. The outer nuclear membrane is contiguous with, and appears to be biochemically similar to, the endoplasmic reticulum (ER).

In contrast, the inner nuclear membrane (INM) contains a unique set of integral membrane proteins that are anchored by association with the nuclear lamina, a network of lamin intermediate filaments underlying the INM. The lamina, together with the associated INM proteins, is thought to act as a scaffold providing structural support for the NE and sites for attachment of inactive heterochromatin to the nuclear periphery.

In addition to its function as a physical barrier, it is now becoming clear that the NE and the associated nuclear lamina play an important role in nuclear stability, chromatin organisation, regulation of tissue-specific gene expression and nuclear-cytoplasmic communication. The diverse functions of the nuclear lamina are made possible through the ability of lamins to interact with a wide range of nuclear proteins involved in different aspects of nuclear function, including the INM proteins, chromatin-associated proteins and transcriptional regulators.

The pivotal role of the lamina has recently been highlighted by the association of a range of tissue-specific inherited disorders, collectively known as laminopathies, with mutations in genes encoding lamins A and C (LMNA) and other lamina-associated proteins. To date, eight LMNA-associated laminopathies have been identified, each involving a different subset of tissues, the major affected tissues being muscle, adipocytes, bone, neurons and skin. Many of the diseases have a devastating effect on the individual, resulting in a significantly shortened lifespan, and the recognised phenotypes include muscular dystrophies, cardiomyopathy, lipodystrophy, neuropathy and several progeroid (premature ageing) disorders.

One of the current challenges it to understand how different mutations in lamin A/C result in such varied disease phenotypes. This will only be achieved by careful dissection of the disease mechanism in each case, together with an increase in our understanding of the basic functions of the nuclear lamins. Our research involves the applications of both of these approaches.

PhD project

The DNA of eukaryotic cells is contained within the nucleus and is separated from the cytoplasm by a double membrane structure, known as the nuclear envelope. Protein components of the nuclear envelope play a critical role in the structural organisation of the nucleus and also in communication between the nuclear interior and the cytoplasm. Their importance is highlighted by the fact that nuclear envelope proteins have been associated with a wide range of human inherited disorders including muscular dystrophies, lipodystrophy (fat wasting), neuropathy and premature ageing syndromes (progeria).

Although around 20 nuclear envelope proteins have now been identified, their precise functions remain poorly understood. The aim of our research is characterise the functions of nuclear envelope proteins and, through this, to gain a better understanding of how mutations in these proteins cause such diverse inherited disorders.

Firstly, we are studying the fat wasting disorder, familial partial lipodystrophy (FPLD). FPLD involves wasting of subcutaneous fat, leading to diabetes and an increased risk of coronary heart disease. We are using transgenic and stem cell technologies to investigate the mechanism of fat loss and identify the molecular defects occurring.

Secondly, we are investigating a novel family of nuclear envelope proteins with a conserved 'SUN' domain, that appear to be involved in nuclear-cytoplasmic communication and nuclear positioning within the cell. Nuclear migration and positioning are vital to many developmental processes. We are using a combination of in vitro, cell culture and transgenic techniques to study SUN protein interactions and their roles in nuclear positioning and human disease.