Norbert Perrimon
Harvard Medical School, Boston, Massachusetts
A signalling scientist marvels at perfect patterns
The formation of patterns during animal development depends to a great extent on cells, or groups of cells, sending a specific signal that activates a cascade of reactions in the cells that receive and respond to it. Studies of this process in the fruitfly Drosophila have provided many insights into the nature of the molecules involved and the mechanisms underlying cell–cell signalling.
The cell surfaces of almost all animals are decorated extensively with large molecules known as heparan sulphate proteoglycans (HSPGs). These modulate most developmental signalling pathways and comprise protein cores modified by the addition of long carbohydrate chains called glycosaminoglycans (GAGs). GAGs are key to mediating interactions between HSPGs and the molecules that they bind.
Recently, Rahul Warrior at the University of California, Irvine, and his colleagues (Development 135, 1039–1047; 2008) explained the puzzling observation that although HSPGs are required for signalling by the protein BMP in certain tissues, they are not required for BMP signalling during very early fly development.
The authors demonstrate that GAG synthesis does not occur in early embryos because the messenger RNAs that encode two enzymes involved in its construction are not translated.Preventing GAG synthesis at this stage allows an 'activity gradient' of BMP to be generated across the embryo that patterns the dorso–ventral axis of the fly. A few hours later, the GAG enzymes are produced, allowing the modified HSPGs to participate in other signalling pathways.
This study illustrates how temporal control of the synthesis of a ubiquitous set of enzymes is used to modulate the activity of signalling pathways in different tissues.
Comments
A great new example of how HSPGs can be precisely regulated to take control over those seemingly ubiquitous growth factors. Heparanase partially releases growth factors immobilized on heparan sulfate GAGs (ie. http://dev.biologists.org/cgi/content/abstract/134/23/4177). By clipping heparan sulfate GAGs, heparanase can also generate or expose a binding site for the new epithelial growth factor 'lacritin' (http://www.jcb.org/cgi/reprint/174/7/1097). Also there is the story of endosulfatases Sulf1 and -2 interfering with Noggin binding (a BMP inhibitor). There are other HSPG stories known and likely soon to be known in this fascinating area of morphogenesis.
Posted by: Gordon Laurie | April 21, 2008 09:10 PM
In order to understand fully action mechanisms of receptors, including large molecules known as heparan sulphate proteoglycans, it is necessary to know that in biological systems, beside the local realm, exists also no local realm, I have discovered and illustrated in a lot of papers (See my website) and also in www.nature.com (e.g., http://blogs.nature.com/nature/journalclub/2008/06/seth_lloyd.html#comments
http://blogs.nature.com/news/thegreatbeyond/2008/06/weekly_round_up_39.html#comments
http://www.nature.com/news/2008/080130/full/451511a.html?q=2#last-comment
http://network.nature.com/forums/harvardpublishingforum/1832?page=1#reply-4955
www.nature.com , http://www.nature.com/news/2008/080130/full/451511a.html
http://www.nature.com/news/2008/080515/full/news.2008.829.html).
Special signals must be sent across a sea of water molecules to the desired partner, and complex mutual structural adjustments (a fluctuation fit) must be completed before each successful binding event. Knowing Quantum Biophysical Semeiotics, one has to recognize that real events are more complex, i.e., difficult to understand, than generally admitted until now. However, the presence of no local realm besides local realm in Biological Systems higlights the patho-physiological mechanisms underlying above-mentioned events. As I illustrated also in The Lancet.com (Stagnaro Sergio. The Lancet, January 28, 2008. Bedside Biophysical-Semeiotic Osteocalcin Test in Diagnosing and Monitoring Diabetes.
http://www.thelancet.com/journals/lancet/article/PIIS0140673608601014/comments?action=view&totalComments=2; Stagnaro Sergio. Il test Semeiotico-Biofisico della Osteocalcina nella prevenzione primaria del diabete mellito. www.fce.it Febbraio 2008. http://www.fcenews.it/index.php?option=com_content&task=view&id=909&Itemid=47) osteocalcin , and all other hormones, cytokines, a.s.o., act upon the related receptors in two diverse action mechanisms: first of all, simultaneously, due to EI (Energy Information), according to Paolo Manzelli (ibidem), and secondly by that manner sufficiently known all around the world, based on the direct contact with related receptors.
Posted by: Sergio Stagnaro MD | July 27, 2008 09:03 AM