Membrane traffic in the post-genomic era

A defining feature of eukaryotic cells is the presence of an elaborate network of internal membrane compartments that communicate between themselves and with the cell surface via specific membrane fission and fusion reactions [1,2]. Such 'membrane trafficking' processes can be viewed as a network of intracellular transport pathways, whose operation is critical to normal physiology and disturbed in disease. A major goal in the field of cell biology, therefore, is to elucidate the mechanistic basis of these fundamental membrane trafficking processes and how they are regulated. Historically, genetic approaches have been instrumental in this effort, particularly forward genetic screens in model eukaryotes, such as budding yeast, by the traditional route of mutagenesis, phenotype selection, and subsequent identification of the affected gene. Such screens have led to the identification of a variety of essential proteins mediating membrane traffic in the biosynthetic pathway of yeast, many of which have orthologs in mammals [3,4].A long-standing barrier to more comprehensive analysis of membrane-trafficking processes in mammalian cells has been the relative intractability of these cells to forward genetic analysis. The main barrier is that mammalian cell culture lines, unlike yeast, cannot be maintained in a haploid state. Therefore, traditional genetic methods based on mutations in the genome, because they typically disrupt only a single copy of a particular gene, rarely produce a screenable phenotype. This barrier is beginning to break down, however, based on the development of alternative methods. The sequencing and annotation of animal genomes, combined with the use of RNA interference (RNAi) to knock down specific gene expression, are ushering in a new era of forward genetic analysis that extends to mammalian cells [5]. A recent study published in Nature from Marino Zerial's group in Dresden (Collinet et al.) [6], illustrates how such approaches are beginning to be ap