Planar cell polarity and morphogenesis. (360G-Wellcome-096645_Z_11_Z)

I pose the main question (A) and subquestions below (B-E). A What are the mechanisms responsible for planar cell polarity (PCP) and how does PCP help build pattern in animals? Most, perhaps all, cells in epithelial sheets are polarised in the plane of the sheet (PCP), as shown by the patterned orientation of mammalian hairs and insect bristles as well as by the consistent polarity of cellular outgrowths such as cilia and stereocilia. The same cellular machinery may also help orient the pla ne of cell division, direct cell movement and possibly regulate the orientation of axon extension [1]. Note that homologous genes have input into PCP of both mice and Drosophila suggesting that the molecular mechanisms are conserved [2]. However we still need a clear picture of these mechanisms. Also, it has been unappreciated that when cells build an animal to what is, in effect, a 3-dimensional specification they need to receive both spatial and vectorial information. This vectorial informatio n may also depend on what we currently call PCP. B. PCP raises a long range question: How is axial information established in a developing embryo or organ and how does it convey polarity to its constituent cells? There is fundamental uncertainty here; we are of the school that thinks that morphogen gradients provide a long range cue, and, if so, PCP would be linked to the basic mechanisms of pattern formation [3]. Others prefer models that depend on a concatenation of local cell interacti ons that spread over the whole organ [4]. We and others have presented evidence that favours our picture but there remains room for doubt. C. PCP also raises a short range question: when a single cell reads polarising information how does it liaise with its neighbours? We know that there are short range interactions: genetic mosaics show that cells that are mutant in PCP genes can change the polarity of nearby wildtype cells [5-7]. We find that the special mechanisms of PCP are revealed by analysing these local interactions in detail. The main techniques are genetics and molecular engineering and these can be combined with staining and tagging to study the distribution of PCP proteins in the cell [6-14]. But we are still a long way from understanding how local polarity signalling works. D. Is PCP involved in growth and specifying proportions? There are two concrete arguments for some connection between PCP and growth; the phenotype of mutants in dachsous (ds) and fat (ft) s how extra growth as well as PCP defects [15-23], and there is a well defined link between Ft, the Hippo pathway and growth [24-30]. We have speculated that the Ds/Ft gradient might be part of a dimension-sensing mechanism [31, 32]. This hypothesis needs more investigation.