Dynamics of the mammalian nucleus: can microscopic movements help us to understand our genes?

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Abstract
The cell is the basic building block of human life. Each of us has existed as a single cell--the fertilized egg--and each of us is made up of billions of cells specialized in many different ways to form our tissues and organs. The nucleus of the cell, described as far back as 1682, is known to be the site of storage of chromosomes that carry the essential and unique DNA blueprint for life. With the recent publication of the entire human genome, our knowledge of exactly what our genes say has increased immeasurably. This, however, is only a small part of the story. In order for the chromosomal genes to function correctly, a complex cellular machinery must rewrite (or transcribe) the genetic instructions of the DNA into a temporary messenger molecule, messenger RNA (mRNA), rearrange (or splice) this message into a readable format and then produce a protein that accurately represents the DNA code. It is these protein molecules that are the functional result of the genetic information. This whole process is termed 'gene expression'. Both transcription and splicing of the mRNA message are carried out in the nucleus. These events must be performed accurately and efficiently in a minute volume already full of highly packaged DNA. An ever-increasing number of sub-nuclear structures have been described, from the nucleolus (first described in 1835) to newly discovered 'paraspeckles' and 'clastosomes'. In fact, as increasing numbers of molecular probes become available, so the complexity of nuclear structure appears to expand. The functions of some of these structures are currently unknown. Those whose functions are, at least partly, understood play roles in gene expression. Interestingly, alterations in nuclear structure are associated with human diseases such as spinal muscular atrophy and promyelocytic leukaemia, suggesting that the control of nuclear organization may be vital to health. The dynamic nature of the structure of the mammalian nucleus has come under increasing scrutiny over the past few years. This has largely been driven by advances in microscopy as well as the advent of in vivo labelling techniques for sub-nuclear structures. It is now possible, using a protein originally isolated from jellyfish, to visualize sub-nuclear structures in living cultured cells. Together with three-dimensional time-lapse microscopy and an ever-expanding range of photo-bleaching techniques, this technology allows us to ask detailed questions about movements of sub-nuclear structures themselves and of the proteins contained within them. It has recently become clear that sub-nuclear structures are capable of moving within the nucleus and of physically interacting with each other. It is also now known that there is a constant flux of molecules into and out of these mobile structures as well as exchange of molecules between them, rather like passengers travelling on the London Underground. The challenge for the future is to relate dynamic events at the microscopic and molecular levels back to the organism as a whole. Only by understanding how the information encoded on genes is accurately expressed at the right time and in the right place can we really take advantage of the knowledge currently available to us.