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| How Cell Communication Activates Cell Division Machinery |
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| SciMed - Biology | |||
| TS-Si News Service | |||
| Wednesday, 07 May 2008 17:00 | |||
 Drosophila is a genus of small flies that belong to the family Drosophilidae. Family members are often called fruit flies (but include vinegar flies, wine flies, pomace flies, grape flies, and picked fruit-flies). Drosophila melanogaster, in particular, has been a model research organism for nearly a century. The species has a relatively short short life span (about two weeks) and a genomic structure that has a number of parallels to human beings. While Researchers study how a complex organism can arise from a relatively simple fertilised egg. There is a great deal of work being done on how various adult structures develop in the pupa (such as the compound eye, wings, legs and other organs). The drosophila egg is about half a millimeter long. • It takes roughly one day after • The larva eats and grows continuously, moulting one, two, and four days after hatching (1st, 2nd and 3rd instars). • After two days as a third instar larva, the larva moults one more time to form an immobile pupa. • Over the next four days, the body is completely remodelled to give the adult winged form, which then hatches from the pupal case and is fertile within about 12 hours. Timing is for 25°C; at 18°C, development takes twice as long. Researchers at the Institute for Research in Biomedicine (IRB Barcelona) performed studies on D. melanogaster, a common fruit fly, to understand the cell proliferation that results in the organized growth of an organ (in this case, the fly wing). The fruit fly wing is a vital experimental model to find future biomedical applications.
A Wingless and Notch double-repression mechanism regulates G1-S transition in the Drosophila wing. Héctor Herranz, Lidia Pérez, Francisco A Martín and Marco Milán. The EMBO Journal 1 May 2008. doi: 10.1038 / emboj.2008.84
The signaling pathways involved in this process are also conserved in humans. When altered in diverse tissues, they can give rise to alternative development and the appearance of different types of cancer, including cancer of the colon and skin, and leukemia. The findings appear in The EMBO Journal, sponsored by the European Molecular Biology Organization (EMBO), and document the distinct signaling pathways that operate between neighboring cells to activate the cell proliferation machinery.
Marco Milán, ICREA Research Professor at IRB Barcelona, led a study team in Milán's Cell and Development Biology Laboratory.
In multicellular organisms, groups of cells assemble to form tissues. Initially homogenous, the field of cells (tissue) subdivides into smaller territories. This is the beginning of a spatial pattern. The subdivision of of D. melanogaster depends on mechanisms that limit cell mixing to produce stable boundaries. These stable subdivisions are called compartments. In the compartments, boundaries serve as signalling centers.
The Notch signaling pathway is a cell signaling system present in most multicellular organisms. The Wnt-Wingless (Wg) pathway is one of a core set of evolutionarily conserved signaling pathways that regulates many aspects of development in multicellular animals. It is a complex network of proteins involved in normal physiological processes in adult animals. It is more commonly known for their roles in embryogenesis and cancer.
The researchers have shown that these two signaling pathways (Notch and Wnt/Wingless) exert control over the cell division machinery through two gene effectors, the proto-oncogen dMyc and the micro-RNA bantam. Regulated by Notch and Wnt/Wingless, these two genes instruct another gene, E2F, to activate the cell division machinery. 
Marco Milán and Héctor Herranz in the Developmental and Growth Control Lab at the IRB Barcelona.
"All of the components were already known but we have clarified the order in the signaling cascade and the interaction between the molecular elements that regulate proliferation for the correct development of the wing", explains Héctor Herranz, first author of the article. Short-range interactions between cells in adjacent compartments induce the expression of the signalling proteins Wingless (Wg) and Decapentaplegic (Dpp) in cells adjacent to the compartment boundaries. Wg and Dpp form long-range extracellular protein gradients centered on the compartment boundaries. Stable boundaries between compartments result in tightly localized sources of these signalling proteins. Intermingling of cells at the compartment boundary causes disorganization of the signalling centre with disastrous consequences for patterning and growth control.
Notch and Wnt/Wingless play a key role in embryo development, cell growth (proliferation) and the transformation of cells into specialized types (
 differentiation). The interesting feature is that these two pathways are highly conserved in humans and whenever mutations arise tumors also appear. Marco Milán goes on to say, "this finding could provide clues about how to repress the cell proliferation signals in cancer". 
Notch activation (green) and cell proliferation (red) in the D. Melanogaster wing primordium.
"All of the components were already known but we have clarified the order in the signaling cascade and the interaction between the molecular elements that regulate proliferation for the correct development of the wing", explains Héctor Herranz, first author of the article.
Furthermore, the research has elucidated the relationship between Notch and Wnt/Wingless in the control of proliferation and the development of the fly wing. In fact, Notch has a repressor function, that is to say, when it is activated the cell division machinery is arrested. Only when Wnt/Wingless starts to work is Notch silenced, thereby triggering the cascade of genes that allow proliferation. “Notch works in this context as a tumor suppressor”, explains Milán, “while Wnt/Wingless acts as an oncogen, that is, by canceling the action of Notch it allows the cell division machinery to operate”. But the fundamental point for the researchers is that Notch and Wnt/Wingless can interchange their roles depending on the context in which they are operating because the true executors of the action are the genes that these proteins regulate, in this case dMyc and bantam. Researchers ask how, for example, in function of the tissue that is affected, Notch can serve as a “tumor suppressor” or as an oncogene. The conclusions drawn from this study, point to effectors being regulated by this pathway. “We have highlighted the importance of the context in which these signaling pathways work and that knowledge about the underlying regulatory elements is crucial to understand how a certain function is performed”, explains Herranz.
The finding made in the fruit fly may provide clues to address problems such as the proliferation of malignant cells and tumour growth in humans. According to Marco Milán, "Diseases like cancer cannot be understood without taking into account how the distinct molecular elements are integrated". He says that diseases like cancer cannot be understood without taking into account how the distinct elements are integrated: that is to say, crosstalk between neighboring cells, effector genes and
cell cycle machinery. “Now we must look for similarities in vertebrates and humans to see whether these elements work in the same way in diseases.”
 The TS-Si News Service is a collaborative effort by TS-Si.org editors, contributors, and corresponding institutions. The sources can include the cited individuals and organizations, as well as TS-Si.org staff contributions. Articles and news reports do not necessarily convey official positions of TS-Si, its partners, or affiliates.We welcome your comments. Use the form below to leave a public comment or send private correspondence via the TS-Si Contact Page. We will not divulge any personal details or place you on a mailing list without your permission. TS-Si is dedicated to the acceptance, medical treatment, and legal protection of individuals correcting the misalignment of their brains and their anatomical sex, while supporting their transition into society as hormonally reconstituted and surgically corrected citizens. 
 
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