Commentary in 2001

Missense mutations in the genes coding for presenilin 1 and presenilin 2 cause familial Alzheimer's disease — a progressive neurodegenerative disorder of the central nervous system. Loss-of-function mutations of these genes in Drosophila, Caenorhabditis elegans and mice cause severe lethal phenotypes, which implicates the presenilins genetically in the Notch signalling pathway. The hypothesis that presenilins are aspartyl proteases that cleave the amyloid precursor protein and Notch can explain the phenotypes. Direct evidence for this hypothesis is, however, difficult to obtain. Moreover, presenilin 1 is a multifunctional protein, as exemplified by its role in the Wnt/β-catenin signalling pathway.

Current models for the export of messenger RNA share the notion that the highly abundant class of nuclear RNA-binding proteins — the hnRNP proteins — have a key role in exporting mRNA. But recent studies have led to a new understanding of several non-hnRNP proteins, including SR proteins and the conserved mRNA export factor ALY, which are recruited to the mRNA during pre-mRNA splicing. These studies, together with older work on hnRNP particles and assembly of the spliceosome, lead us to a new view of mRNA export. In our model, the non-hnRNP factors form a splicing-dependent mRNP complex that specifically targets mature mRNA for export, while hnRNP proteins retain introns in the nucleus. A machinery that is conserved between yeast and higher eukaryotes functions to export the mRNA.

For the cell biologist, identifying changes in gene expression using DNA microarrays is just the start of a long journey from tissue to cell. We discuss how chip users can first filter noise (false-positives) from daunting microarray datasets. Combining laser capture microdissection with real-time polymerase chain reaction and reverse transcription is a helpful follow-up step that allows expression of selected genes to be quantified in populations of recovered cells. The voyage from chip to single cell can be completed using sensitive new in situ hybridization and immunohistochemical methods based on tyramide signal amplification.

Since the discovery of substances in serum media that are able to drive cells into proliferation and/or differentiation, investigators have tried to understand how such signalling molecules can influence cells to change their behaviour. The complex nature of the responses to signals, and the equally complex signalling pathway leading to those responses, have made life difficult for the researcher. However, recent evidence obtained in genetic developmental systems indicates that a multiplicity of downstream events can be accomplished by regulation of the activity of just one transcription factor.

Morphogens are in the front line just now. Here I trace how the concept of a morphogen has evolved over the past 100 years and step a little beyond what we already know.

The process of cell division, or mitosis, has fascinated biologists since its discovery in the late 1870s. Progress through mitosis is traditionally divided into stages that were defined over 100 years ago from analyses of fixed material from higher plants and animals. However, this terminology often leads to ambiguity, especially when comparing different systems. We therefore suggest that mitosis can be re-staged to reflect more accurately the molecular pathways that underlie key transitions.