The Direction of Cell Polarity

Cell Polarity By Drubin David G. Oxford: Oxford University Press (2000). 344 pp. $55.00Cellular asymmetry, or cell polarity, is integral to the development and functioning of all organisms from bacteria to humans. Modern methods have fueled tremendous advances in our understanding of the mechanisms underlying the generation of cell polarity. In recent years a number of reviews, including those contained in this collection, have captured and distilled the progress that has been made in a manner useful to both students and those already in the field. This collection acquaints the reader with the diversity of systems in which questions of cell polarity and organization are being tackled. The reviews progress from the simple to the complex, from bacteria to metazoans. Most reviews center around organisms or cell types: bacteria, yeasts, ciliates, epithelia, plant cells, Xenopus, and skin epithelia. Several are centered on themes: chemotaxis, exocytosis, and asymmetric cell division (yeast, C. elegans, Drosophila). For the most part, the reviews effectively get the reader up to speed on both background and recent developments.As this collection attests, remarkable progress has been made. In systems such as budding yeast, it is now possible to trace a pathway from an initial spatial cue to the cytoskeleton (as reviewed in the chapter by Bahler and Peter, “Cell Polarity in Yeast”). For instance during mating, which requires chemotropic polarization toward a prospective partner, pheromone secreted by a cell of one mating type binds to a seven transmembrane receptor on the surface of a partner of the opposite mating type. Pheromone-bound receptor activates a G protein in a spatially restricted manner to release its βγ subunit, which then recruits an adaptor protein Far1. Far1 in turn recruits Cdc24, the exchange factor for the Rho-type GTPase Cdc42. The resulting local activation of Cdc42 causes polarized assembly of the actin cytoskeleton, likely via the actin-related protein (ARP) complex. Five years ago, our mechanistic understanding of this polarization pathway and essentially all others was murky at best. This volumes describes the progress that has been made and prepares the reader to anticipate what is to come.Although lacking molecular detail, the chapter by Frankel, “Cell Polarity in Ciliates,” is an especially welcome inclusion given the fascinating contributions of work in ciliates to concepts of epigenetic inheritance. One particularly dramatic example is the stable inheritance of the ciliary row orientations on the surface of Paramecium and other ciliates. Vertical rows of ciliary units, parallel to the longitudinal axis of the cell, have a vectorial polarity because each ciliary unit is itself asymmetrical and points toward the anterior end of the cell. On occasion a perturbation gives rise to an inverted row (pointing toward the posterior). Row inversions can be stably propagated for thousands of cell divisions without any conventional genetic changes. Such stable inheritance occurs because new ciliary units are added to a template, the existing row, and because cytokinesis occurs perpendicular to the long axis of the rows thereby endowing each progeny with half of each existing row. Frankel's chapter compels the reader to consider the influence of epigenetic inheritance in other cellular systems where its manifestations may not be so obvious and is certainly worthwhile reading.I also found particularly interesting a discussion of how shallow gradients might be reliably translated into axes of cell polarity in the review by Weiner, Servant, Parent, Devreotes, and Bourne (“Cell Polarity in response to chemoattractants”). How is a minute difference in the concentration of a chemoattractant across a cell transformed into an all-or-none axis? The authors reason that short-range positive feedback with long range inhibition must be built into the machinery (Turing, Bull. Math. Biol. 52, 153–197, 1990; Gierer and Meinhardt, Kybernetik 12, 30–39, 1972; Meinhardt and Gierer, J. Cell Sci. 13, 321–346, 1974). They attempt to pinpoint the step in signaling at which this regulation might be occurring. This discussion highlights the broader challenge to reexamine the actual physiology of cells in the context of all of the emerging molecular information. Investigators will have to ask how (or whether) the molecular machinery, as known, can explain the sophisticated cellular behaviors observed.Reading this collection of reviews brought to mind two general questions concerning cell polarity. To what extent is there a unifying theory of cell polarity? And what areas will see major advances in future years? Cell biologists are primed to expect conservation of mechanism. Perhaps this expectation was produced by the elucidation of cyclin-dependent kinase modules as the unifying theme in driving the eukaryotic cell cycle over a decade ago. Shall there be a unifying mechanism underlying the generation of cell polarity? To a certain extent, the answer to this question depends on ones initial bias and upon the stage of the process being considered. Cell polarity can be thought of in simple terms as the transmission of spatial cues, internal or external, to organize the cytoskeleton. Clearly the highest level of conservation is in the cytoskeleton; all eukaryotes contain actin and microtubule cytoskeletons. Even bacteria appear to rely on a structural protein FtsZ, which is distantly related to tubulin (Erickson, Cell 80, 367–370, 1995). There appears to be less conservation in components in each step removed from the cytoskeleton. For the actin cytoskeleton, the actin-related protein (ARP) complex and Rho-type GTPases are conserved from yeast to humans. As one looks upstream from Rho type GTPases to the interface of signal transduction and spatial cues, much of the machinery is not conserved. For example, the Bud proteins that act as landmarks to direct patterns of polarization and division in yeast are not conserved in other eukaryotes. Far1 protein, the key link between G protein signaling and polarity establishment in yeast has no cognate homolog in higher cells. A conspicuous exception to this broad generalization is perhaps the seven transmembrane receptors as upstream transducers of a large number of chemotactic or chemotropic signals. Then again, these receptors impinge upon almost all aspects of cellular physiology. As a rough generalization, diverse spatial signals and landmarks act via regulatory networks, which converge on the conserved central machinery of the cytoskeleton.Where is the richest frontier for examining the mechanisms of cell polarity and organization? Oddly enough, bacteria, the simplest of the systems examined in this volume, should witness the largest fundamental advances. Only recently has the field of prokaryotic cell biology emerged with the molecular organizations of bacteria being fully appreciated. However, we still know very little. Bacterial chromosomes separate as if driven by an active mechanism, but the basis of this movement is completely opaque (Gordon et al., Cell 90, 1113–1121, 1997; Webb et al., Cell 88, 667–674, 1997). Imagine eukaryotic cell biology without knowledge of the spindle. An excellent illustration of further surprises in store is the recent finding that regulators of bacterial cellular architecture exhibit extremely rapid dynamics. MinD, a regulatory protein that prevents division at the poles of E. coli, can be seen concentrated at one pole or the other of this rod-shaped bacterium. Amazingly, MinD localization appears to oscillate between poles every 20 s—this is unexpected to say the least (Raskin and de Boer, Proc. Natl. Acad. Sci. USA 96, 4971–4976, 1999).Like the movements of the MinD protein, rapid movements are occurring in the intellectual landscape of cell biology, and cell polarity is no exception. This volume is a snapshot of the field as it currently stands, and it whets our appetites for the advances sure to come in the next five years.