|BioResearch Suggests Refinements To Morphogen Theory|
|SciMed - Biology|
|TS-Si News Service|
|Friday, 27 April 2012 02:00|
New York, NY, USA. New mechanisms that control protein expression in different regions of embryos shed additional insight into how physical traits are arranged in body plans.
The findings, which appear in the journal Cell, call for reconsideration of morphogen theory, which posits that proteins controlling traits are arranged as gradients, with different amounts of proteins activating genes to create specified physical features.
Morphogen Theory contends that physical features are necessarily tied to absolute concentrations of proteins within the morphogen gradient. A morphogenic substance oversses tissue development and the correct positioning of specialized cell types within a tissue. Under the theory, if a certain critical mass of protein is present, then a given physical feature for example, cells that make the skin on your forehead will appear. If less than that critical mass is present, a different structure say, the skin that makes your eyebrows will appear, and a boundary will be formed between the two structures.
Alan Turing (23 June 1912 – 7 June 1954), the mathematician and code breaker, first proposed morphogen theory in the 1950s. Refined in the 1960s by Lewis Wolpert, the theory has been used to explain why a tiger has stripes, among other phenomena.
The current research does raise questions about the theory, but the NYU bologists say their findings did not falsify it, but rather suggest morphogen theory needs some additional refinement.But some biologists have raised questions, offering alternative views suggesting that physical features are not necessarily the result of a specified number of proteins, but, rather, come from more complex interactions between multiple gradients that work against one another.
Biologists from New York University (NYU) explored this process by studying the fruit fly Drosophila, a powerful model for studying genetic development as it is amenable to precise genetic manipulations. They focused on one protein, Bicoid (Bcd), which is expressed in a gradient with highest levels at the end of the embryo that will become the mature fly's head.
The researchers, headed by Stephen Small, chair of NYU's Department of Biology, examined a large number of target genes that are directly activated by Bcd. Each target gene is expressed in a region of the embryo with a boundary that corresponds to a specific structure.
By examining DNA sequences associated with these target genes, the NYU researchers discovered binding sites for three other proteins Runt, Capicua, and Kruppel which all act as repressors. All three proteins are expressed in gradients with highest levels in the middle part of the embryo, and thus are positioned in exactly the opposite orientation compared to the Bcd activation gradient.
By changing the spatial distribution of the repressors and by manipulating their binding sites, Small and his colleagues showed that these repressors antagonize Bcd-dependent activation and are absolutely critical for establishing the correct order of boundaries that are found in a normal embryo.
In other words, contrary to Turing's theory, a single gradient of proteins does not have sufficient power to form the same body plan in each member of a species; however, if there are multiple gradients that work against each other, then the system becomes robust enough for normal development.
ParticipationThe study's other co-authors were Constance Mei, an undergraduate at New York University (NYU) at the time of the study who received her bachelor's degree in 2011; current NYU doctoral students Hongtao Chen and Zhe Xu; and Danyang Yu, who received her doctorate in biology from NYU in 2009 and who is now an assistant professor of biology at Farleigh Dickinson University (FDU).
CitationA System of Repressor Gradients Spatially Organizes the Boundaries of Bicoid-Dependent Target Genes. Hongtao Chen, Zhe Xu, Constance Mei, Danyang Yu, Stephen Small. Cell 2012; 149(3): 618-629. doi:10.1016/j.cell.2012.03.018
● A Runt protein gradient represses Bicoid-dependent activation in Drosophila embryos
● Runt and two other repressors spatially position Bicoid target gene boundaries
● At least one repressor binds directly to all 66 known Bicoid-dependent enhancers
● The repression system puts conceptual limits on the Bicoid morphogen hypothesis
The homeodomain (HD) protein Bicoid (Bcd) is thought to function as a gradient morphogen that positions boundaries of target genes via threshold-dependent activation mechanisms. Here, we analyze 66 Bcd-dependent regulatory elements and show that their boundaries are positioned primarily by repressive gradients that antagonize Bcd-mediated activation. A major repressor is the pair-rule protein Runt (Run), which is expressed in an opposing gradient and is necessary and sufficient for limiting Bcd-dependent activation. Evidence is presented that Run functions with the maternal repressor Capicua and the gap protein Kruppel as the principal components of a repression system that correctly orders boundaries throughout the anterior half of the embryo. These results put conceptual limits on the Bcd morphogen hypothesis and demonstrate how the Bcd gradient functions within the gene network that patterns the embryo.
|Last Updated on Friday, 27 April 2012 02:55|