How Stem Cells Produce Different Kinds of Cells

How Stem Cells Produce Different Kinds of Cells

Sunday, 05 May 2013

The human body contains trillions of cells, all derived from a single cell, or zygote, made by the fusion of an egg and a sperm. That single cell contains all the genetic information needed to develop into a human, and passes identical copies of that information to each new cell as it divides into the many diverse types of cells that make up a complex organism like a human being.

If each cell is genetically identical, however, how does it grow to be a skin, blood, nerve, bone or other type of cell? How do stem cells read the same genetic code but divide into very different types?

The apical tip of fruit fly testis containing germ line 

stem cells and differentiating germ cells. Copies of 

Y chromosome are marked with either red or blue. 

Using this method, the authors discovered that 

germ line stem cells inherit specific copies of Y (and 

X) chromosomes. Credit: Yukiko Yamashita. 

Researchers at the University of Michigan have found the first direct evidence that cells can distinguish between seemingly identical copies of chromosomes during stem cell division, pointing to the possibility that distinct information on the chromosome copies might underlie the diversification of cell types.

Scientists in the lab of Life Sciences Institute researcher Yukiko Yamashita explained how stem cells can distinguish between two identical copies of chromosomes and distribute them to the daughter cells in a process called non-random chromosome segregation. They also described the genes responsible. Their work is scheduled to be published online May 5 in Nature.

"If we can figure out how and why cells are dividing this way, we might be able to get a glimpse of how we develop into a complete human, starting from a single cell," Yamashita said.

"It is very basic science, but understanding fundamental biological processes always has wide-ranging implications that could be exploited in therapeutics and drug discovery."

During the cell division cycle, the mother cell duplicates its chromosomes, generating two identical sets. When the cell divides to become two cells, each cell inherits one set of chromosome copies. In many divisions, the daughter cells are identical to the mother — one skin cell becomes two, for instance.

But in a process called asymmetric division, a cell divides into two daughters that are not identical — a skin stem cell divides into another skin stem cell and a regular skin cell, for example. In that case, the genetic information within the chromosome copies remains the same, but the type of cell, or "cell fate," is different.

The Yamashita lab used stem cells from the testes of the fruit fly Drosophila to study the process of cell division.

"The Drosophila germ line stem cell can be identified at a single-cell resolution, so they are an ideal model," Yamashita said.

The stem cells cluster and are easy to identify; they divide to produce another germ line stem cell and a differentiating cell called a gonialblast, which goes on to eventually become a sperm cell.

The researchers marked the copies of each chromosome in the Drosophila stem cells as they divided. Using this method, they tracked the tendency of the X and the Y chromosome copies to move to the daughter germ line stem cell or to the gonialblast. They were able to demonstrate that copies of X and Y chromosomes (but not other chromosomes) are distinguished and delivered to the daughter cells with a striking bias.

This is the first direct evidence that cells indeed have an ability to distinguish identical copies of chromosomes and separate them in a regulated manner. This ability has been suspected and hypothesized, but never proven.

"We do not know yet why copies of X and Y chromosomes segregate non-randomly," Yamashita said.

"We think maybe specific epigenetic information is transmitted to the germ line stem cell and to the gonialblast."

The findings suggest that the information on the X and Y chromosomes that makes this division possible is primed during gametogenesis — the process of creating ovum or sperm cells — in the parents.

Many other cells throughout the body are able to divide into two different types, especially during embryonic development. Yamashita's next steps are to explore whether the non-random chromosome segregation seen in Drosophila is a widespread phenomenon that is shared by mammals, including humans.

Source: University of Michigan 

Contact: Laura J. Williams

Reference:

Chromosome-specific nonrandom sister chromatid segregation during stem-cell division

Swathi Yadlapalli &  Yukiko M. Yamashita

Nature (2013), doi:10.1038/nature12106

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Scientist Identifies Protein Molecule Used to Maintain Adult Stem Cells in Fruit Flies

Scientist Identifies Protein Molecule Used to Maintain Adult Stem Cells in Fruit Flies 
Tuesday, 23 April 2013

Understanding exactly how stem cells form into specific organs and tissues is the holy grail of regenerative medicine. Now a UC Santa Barbara researcher has added to that body of knowledge by determining how stem cells produce different types of "daughter" cells in Drosophila (fruit flies). The findings appear today in the Proceedings of the National Academy of Sciences.

Denise Montell, Duggan Professor of Molecular, Cellular and Developmental Biology at UCSB, and colleagues studied the ovaries of fruit flies in order to see stem cells in their natural environment. Because these organisms are excellent models for understanding stem cell biology, researchers were able to shed light on the earliest stages of follicle cell differentiation, a previously poorly understood area of developmental biology.

"It is clear that the fundamental principles that control cell behaviour in simple animals are conserved and control the behaviour of our cells as well," she said.

"There is so much we can learn by studying simple organisms."

This is a schematic drawing of a 

Drosophila ovariole and a magnified

germanium. Credit: UCSB. 

Using a nuclear protein expressed in follicle stem cells (FSCs), the researchers found that castor, which plays an important role in specifying which types of brain cells are produced during embryonic development, also helps maintain FSCs throughout the life of the animal.

"Having identified this important protein molecule in fruit flies, we can test whether the human version of the protein is important for stem cells and their daughters as well," said Montell.

"The more we know about the molecules that govern stem cell behaviour, the closer we will get to control these cells."

This image shows Denise Montell,

University of California, Santa Barbara.

Credit: George Foulsham, UCSB. 

Her research team placed the evolutionarily conserved castor (Cas) gene, which encodes a zinc finger protein, in a genetic circuit with two other evolutionarily conserved genes, hedgehog (Hh) and eyes absent (Eya), to determine the fates of specific cell progeny (daughters). What's more, they identified Cas as a critical, tissue-specific target of Hh signalling, which not only plays a key role in maintaining follicle stem cells but also assists in the diversification of their progeny.

The study also shows that complementary patterns of Cas and Eya reveal the gradual differentiation of polar and stalk precursor cells at the earliest stages of their development. In addition, it provides a marker for cell fates and insight into the molecular and cellular mechanisms by which FSC progeny diverge into distinct fates.

Follicle cells undergo a binary choice during early differentiation. Those that turn into specialized cells found at the poles of egg chambers go on to make two cell types: polar and stalk. The three genes, Cas, Eya and Hh, work in various combinations, sometimes repressively, to determine which types of cells are formed. Cas is required for polar and stalk cell fate specification, while Eya is a negative regulator of these cells' fate. Hh is necessary for Cas to be expressed, and Hh signalling is essential to repress Eya.

"If you just had one of these markers, it was hard to tell what's going on," explained Montell.

"All the cells looked the same and you had no idea when or how the process occurred. But now we can actually see how the cells acquire different identities."

Hh also plays many roles in embryonic development, adult homeostasis, birth defects, and cancer. Hh antagonists are currently in clinical trials for the treatment of several types of cancer. However, Hh signalling is important in so many different cell types and tissues that systemic delivery of such inhibitors may cause serious side effects. Therefore identifying the essential, tissue-specific effectors of Hh has the potential to lead to the identification of more specific therapeutic targets.

Someday, targeted inhibition of Hh signalling may be effective in the treatment and prevention of many types of human cancers.

Source: University of California - Santa Barbara 

Contact: Julie Cohen

Reference:

Castor is required for Hedgehog-dependent cell-fate specification and follicle stem cell maintenance in Drosophila oogenesis

Yu-Chiuan Chang, Anna C.-C. Jang, Cheng-Han Lin, and Denise J. Montell

PNAS 2013 ;  April 22, 2013, doi:10.1073/pnas.1300725110

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Genes Have Help in Determining Our Traits

Yale scientists find that a type of RNA together with a common protein to protect organisms from harmful genetic variations
Monday, 27 December 2010

For decades, biology textbooks have been clear – our traits are the product of our genes. But a new study by Yale University researchers published Dec. 26 in Nature Genetics suggests another mechanism can regulate variations of traits even in genetically identical individuals.

A particular type of RNA works in concert with a common protein to protect organisms from harmful genetic variations without the help of genes, reports Haifan Lin, director of the Yale Stem Cell Center, professor of cell biology and genetics and senior author of the paper.

“This mechanism may help explain how ordinary cells such as fibroblasts can be converted to stem cells and why some cancers develop at random,” Lin said.

The theory that factors other than genes are responsible for an organism’s traits, or phenotype, has been around for almost 70 years but has only gained steam in the past decade. For instance, cloned animals are often born with different colours than the animals that are the source of their DNA. But what causes these changes remained unclear.

About a decade ago, scientists found that a noticeable percentage of flies lacking a protein called Hsp-90 ended up with bizarre and random abnormalities such as legs growing where eyes should be. It seemed clear that Hsp-90 protected an organism against harmful genetic variations in its genome. Yet, since Hsp-90’s role is to mobilize other molecules to respond to stress, researchers suspected other factors were involved.

One school of thought suspected that Hsp-90 prevents the display of random abnormalities by suppressing the activities of “jumping genes” that can relocate to other areas of the genome and cause mutations. However, the Yale researchers report that their work with flies shows that a type of small RNA called Piwi-interacting RNA, or piRNA, acts in concert with Hsp-90 and another molecule to prevent both the creation of variants and the activation of existing genetic variants. Genes do play a role in protecting against harmful variations but probably work through actions of the molecules piRNA and Hsp-90.

Lin, who studies piRNAs in reproductive cells and stem cells, says that the variations in levels of Hsp-90 and piRNAs among individual cells of the same type might explain why a small number of ordinary cells can be reprogrammed into stem cells and also why harmful mutations are created in some cancers.

“This study shows that we still have a lot to learn about the most basic principles of gene regulation,” Lin commented.

“Studies of this kind may provide missing puzzles in our understanding of normal development and malignancies.”

Source: Yale University
Contact: Bill Hathaway

Reference:
Drosophila Piwi functions in Hsp90-mediated suppression of phenotypic variation
Vamsi K Gangaraju, Hang Yin, Molly M Weiner, Jianquan Wang, Xiao A Huang & Haifan Lin
Nature Genetics, 26 December 2010, doi:10.1038/ng.743
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New Mechanism Regulating Embryonic Development Discovered

New Mechanism Regulating Embryonic Development Discovered Wednesday, 10 March 2010 A Princeton University-led research team has discovered that protein competition over an important enzyme provides a mechanism to integrate different signals that direct early embryonic development. The work suggests that these signals are combined long before they interact with the organism's DNA, as was previously believed, and also may inform new therapeutic strategies to fight cancer. The fought-over enzyme, known as the mitogen-activated protein kinase (MAPK), is found in all complex organisms, ranging from yeast to humans. MAPK signalling pathways, or chemical networks that involve the enzyme, are critical for normal development, and defects in these pathways can lead to severe developmental disorders and cancer. During early embryonic development, a single undifferentiated cell becomes a complex and highly specialized organism containing a variety of different cell types arranged in very precise patterns. These patterns, which ensure that the body structures from head-to-tail and front-to-back develop correctly and in the appropriate places, are created when cells respond to a series of chemical signals from different signalling pathways. The different patterning signals received by any given cell are ultimately combined to govern its future fate and tell it what kind of cell it should become. Until now, scientists believed these pathways operated largely independently of one another to produce protein signals that travelled to the nuclei of the embryo's cells where DNA is stored. There, coordination of these signals was thought to occur when they interacted with cell DNA to influence and control the expression of genes. Results published March 9 in the journal Current Biology, however, suggest that competition for the MAPK enzyme among proteins in different pathways influences which signals are sent to cells, establishing a biochemical mode of signal integration that adds a previously unrecognized layer of complexity and control to embryonic development.

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The Princeton team used confocal microscopy to visualize the spatial distribution of two proteins that compete for the MAPK enzyme in early fruit fly embryos. In areas where levels of a protein important for the development of the head were high (shown here in red, with brighter colour indicating the presence of more protein) there was less enzyme available to act upon a different protein (shown here in blue) that is important for the development of the ends of the embryo, including the tail. Credit: Princeton University/Shvartsman Lab. A second protein (shown here in blue) is important for the development of the ends of the embryo, including the tail. Credit: Princeton University/Shvartsman Lab.

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"It appears that different proteins in different pathways are competing for the MAPK enzyme inside these living organisms," said Stanislav Shvartsman, associate professor in the Department of Chemical Engineering and the Lewis-Sigler Institute for Integrative Genomics who earned his Ph.D. from Princeton in 1999. "Since these proteins are fighting for the same limited resource – the enzyme – they indirectly control one another, which in turn coordinates the developmental signals." Conventional biology teaches that enzymes like MAPK act on certain molecules, called substrates, to regulate chemical reactions. The new findings are surprising because it appears that, through competition with one another, the substrates of MAPK are, in fact, influencing the enzyme's activity. "In a way, it's like the tail wagging the dog," Shvartsman said. "The substrates are regulating the enzyme, and, by extension, mediating the chemical reactions." Eric Wieschaus, Princeton's Squibb Professor in Molecular Biology who received the 1995 Nobel Prize in medicine for his pioneering work in developmental biology, said: "Their results argue convincingly that these signalling molecules are interacting with each other in a competitive way such that even before anything gets to the DNA, they've already made decisions. Essentially the decisions aren't just made in terms of DNA, but also in terms of proteins working together. This is, in a way, revolutionary." The research team, led by Princeton chemical engineering graduate student Yoosik Kim, focused its attention on the interaction between MAPK and two proteins involved in two different signalling pathways for head-to-tail pattern formation. The first of these proteins is part of the pathway that governs the development of the head. The second protein plays a significant role in the chemical circuit that controls the development of the ends of the embryo, including the tail. Using special techniques to visualize whether the proteins had interacted with the MAPK enzyme, the team found that the relative amount of the first protein controlled how much enzyme was available to interact with the second protein. For example, in the portion of the embryo that would become the head, where the concentration of the first protein was high, much less enzyme was available to act on the second protein than at the other end of the embryo, where the tail would ultimately develop. "This competition makes sure that the same enzyme signals are interpreted differently in the head and in the tail, thereby allowing for the integration of multiple signals," Shvartsman said. Based on how the enzyme interacted with the proteins in the head region of the embryo, the team predicted that a third protein also might be competing for the MAPK enzyme in that area. To test the hypothesis, research team members at the Institute for Medical Research Israel-Canada at Hebrew University in Jerusalem used a series of experimental techniques to verify that their proposed protein could bind to the enzyme, an ability that was previously unknown. These findings suggest that the competition model may provide a novel way to identify proteins that are involved in signalling pathways. Beyond advancing the fundamental understanding of mechanisms that control embryonic patterning, the work has implications for how to target cancer cells, which often exhibit hyperactive MAPK signalling. "According to our substrate competition idea, MAPK signalling activity directed toward any given substrate decreases when you introduce a competing substrate," Kim said. "In theory, you can lower the activity of MAPK if you introduce a protein whose sole function is to bind to MAPK and thus act as a competitive inhibitor of MAPK signalling to all other substrates." This strategy might one day allow scientists to slow or stop MAPK signalling pathways in cancer cells by adding a protein that monopolizes the MAPK enzyme, effectively disrupting the chemical circuitry of a cancer cell. In future work, the researchers plan to conduct experiments to investigate competition among other proteins that bind to MAPK and to investigate how this competition for the MAPK enzyme manifests itself in other organisms. The group also intends to explore how certain proteins are able to out-compete other proteins for the enzyme's attention, perhaps by binding more strongly or efficiently to the molecule. In time, the group may expand its work to consider whether similar competition models affect the activity of different enzymes in other signalling pathways. Reference: MAPK Substrate Competition Integrates Patterning Signals in the Drosophila Embryo Yoosik Kim, Mathieu Coppey, Rona Grossman, Leiore Ajuria, Gerardo Jiménez, Ze'ev Paroush, Stanislav Y. Shvartsman Current Biology, Volume 20, Issue 5, 446-451, 18 February 2010, 10.1016/j.cub.2010.01.019 ......... ZenMaster

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How an Enzyme Tells Stem Cells Which Way to Divide

University of Oregon biochemists report a mechanism dictating cell division is not a long cascade of events Thursday, 14 May 2009 Driving Miranda, a protein in fruit flies crucial to switch a stem cell's fate, is not as complex as biologists thought, according to University of Oregon biochemists. They've found that one enzyme (aPKC or atypical protein kinase C) stands alone and acts as a traffic cop that directs which roads daughter cells will take. "Wherever aPKC is at or on a cell's cortex or membrane, Miranda isn't," says Kenneth E. Prehoda, a professor in the chemistry department and member of the UO's Institute of Molecular Biology. When a stem cell duplicates into daughter cells, the side, or cortical domain, containing aPKC continues as a stem cell, while the other domain with Miranda becomes a differentiated cell such as a neuron that forms the central nervous system. Prehoda and co-author Scott X. Atwood, who studied in Prehoda's lab and recently earned his doctorate, describe how the mechanism works in the May 12 issue of the journal Current Biology. Instead of a complex cascade of protein deactivation steps that many biologists have theorized, Prehoda said, aPKC strips phosphate off an energy-transfer nucleotide known as ATP and then attaches it to Miranda. This process forces Miranda away from aPKC and helps determine the fates of subsequent daughter cells. "This process is pretty simple," he said, when viewed from a biochemical perspective. "What happens is that Miranda gets phosphorylated by aPKC, turning it into an inactivated substrate and pushing it into another location in the cell."

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Dividing Drosophila neuroblast. aPKC is shown in green at the top half of a fruit fly neuroblast. Miranda, in blue, has been driven away to the opposite side. Upon division, the top half will remain a stem cell, while the bottom will become a differentiated cell. Credit: Courtesy of Kenneth Prehoda.

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Much of the paper in Current Biology is devoted to discuss why the more complex scenarios are not accurate. "There have been a lot of ideas on how this works, and most seemed to be really complicated and difficult to explain. We have found it's a much simpler mechanism," Prehoda said, adding that the mechanism likely is similar in many other types of cells, not just stem cells. "It's a basic-research question. How does this polarity occur? In order to develop stem cell-specific therapeutics based on a rational methodology you have to understand the mechanism," he said. If Miranda is improperly isolated into other regions by aPKC, the stem cell divides symmetrically, with both daughter cells adopting the same fate, In turn, Prehoda said, these cells can become tumours as they continue to rapidly divide without proper polarization. ......... ZenMaster

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Are Bigger Genomes Better?

With genomes, bigger may really be better Wednesday, 04 March 2009 Biologists analyzing DNA in search of the molecular underpinnings of life have consistently favoured species with small genomes, which are cheaper to sequence and lack the repetitive "junk" that clutters bigger genomes. But a new study by Howard Hughes Medical Institute scientists suggests that when it comes to figuring out how genes are controlled, bigger genomes are much more useful. Animal genomes vary tremendously in size; worms have as few as 70 million "letters" of DNA, whereas salamanders have more than 100 billion. In a research article published in Public Library of Science (PLoS) One on March 4, 2009, Howard Hughes Medical Institute investigator Michael B. Eisen and colleagues report that large genomes can make it easier to find regions of DNA that control gene activity. "In small genomes, functional elements are packed tightly together. In bigger genomes functional elements are separated and therefore easier to find," says Eisen, who collaborated on the study with scientists at the University of California, Berkeley, the University of Arizona, and the Pacific Basin Agricultural Research Center of the U.S. Department of Agriculture. A genome is like a recipe for a meal that comes with two sets of instructions. One set shows how to make the ingredients for the meal - the proteins that constitute living things. The second set shows how to measure, mix, and cook the ingredients - that is, when and where proteins should be manufactured to carry out biological processes. The first set of instructions is relatively easy to identify and read, but the second set has been more elusive. "We don't understand how regulatory information is written in the genome, and in most cases we don't even know where to look." says Eisen. Only a small fraction of the tens of thousands of regulatory sequences in the human genome has been identified. Most of these have emerged from studies comparing the human genome to those of mice, chickens, fish, and other vertebrates. Many of the small pieces of DNA shared by these distantly related species have proven to be involved in gene regulation. To understanding the function of such regulatory sequences, Eisen and other geneticists have turned to model invertebrate species like the fruit fly Drosophila melanogaster. However, the shortcut used to identify regulatory sequences in humans has never worked well in Drosophila. While comparisons among Drosophila genomes identify many shared sequences, the rapidly evolving DNA that separates these conserved sequences in vertebrates is largely absent in Drosophila, making it difficult to tell where one regulatory sequence ends and the next begins. When Eisen and his Berkeley colleagues went hunting for regulatory sequences in the genomes of Drosophila's distantly related fly cousins, they didn't expect genome comparisons to be the key. However, when graduate students Brant Peterson and Emily Hare compared pieces of the genomes of the medfly and the melon fly, two agricultural pests in the family Tephritidae, they noticed that these comparisons looked just like those seen in vertebrates. The difference, Eisen says, is in the size of their genomes. Drosophila genomes are twenty times smaller than the human genome, and have been purged of non-functional DNA. But tephritid genomes are five times bigger than Drosophila genomes, and not nearly so streamlined. "I'd love to say we chose the tephritids with this in mind, but it was totally serendipitous," says Eisen. "The fact that the tephritids had big genomes was originally a nuisance because we had to do more sequencing and more screening. It was only after we got the data that we realized this might actually be an advantage." Based on earlier human work, Peterson hypothesized that the well separated blocks of conserved DNA in tephritids were regulatory sequences. Since there was no method available for testing these sequences in tephritids, Peterson inserted them into the laboratory mainstay Drosophila melanogaster. More than 150 million years of evolution separate tephritids from Drosophila melanogaster, but six of the nine pieces of conserved tephritid DNA functioned as regulatory sequences in the fruit fly. Furthermore, Peterson found matches for each of the tephritid sequences in the Drosophila melanogaster genome, and showed that the matched tephritid and Drosophila sequences drive the same patterns of gene expression. Thus, it may be easier to identify regulatory sequences in the widely studied Drosophila melanogaster genome by sequencing and comparing tephritid genomes than sequencing more Drosophila genomes, Eisen says. The findings have broader implications, too, Eisen says. Many biologists have been left with the impression that gene regulation is simpler in invertebrates than in vertebrates, since virtually all sequenced invertebrate genomes are small, with compact regulatory regions, and most sequenced vertebrate genomes are big. But Eisen points out that the sequenced invertebrate genomes are not representative. With limited funds available to study species not closely related to humans, and with the cost of genome sequencing scaling directly to genome size, the myriad invertebrate species with large genomes have been shunned. "While the idea that there is a fundamental difference in the complexity of vertebrate and invertebrate genomes fits with our anthropocentrism," says Eisen, "it does not appear to be true. It's an illusion created by a bias towards sequencing small genomes whenever possible." Eisen is optimistic that observations from studies like this, together with the rapidly dropping cost of sequencing, will reverse this bias, allowing researchers to generate a clearer picture of the structure and evolution of animal genomes. To aid in that goal, he is working with scientists from the Department of Agriculture and Baylor College of Medicine to sequence complete tephritid genomes. Reference: Big Genomes Facilitate the Comparative Identification of Regulatory Elements Brant K. Peterson, Emily E. Hare, Venky N. Iyer, Steven Storage, Laura Conner, Daniel R. Papaj, Rick Kurashima, Eric Jang, Michael B. Eisen PLoS ONE 4(3) (2009): e4688. doi:10.1371/journal.pone.0004688 ......... ZenMaster

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How Cells Communicate in Cell Division

Intricate network of regulatory functions explained Monday, 05 May 2008 A new study reveals how cells communicate to activate the cell division machinery. 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. The study was performed by researchers at the Institute for Research in Biomedicine (IRB Barcelona) on the fruit fly, Drosophila melanogaster, and unveils how distinct signalling pathways operate between neighbouring cells in order to activate the cell proliferation machinery that results in the organized growth of the fly wing. The signalling pathways involved in this process are also conserved in humans, and when altered in diverse tissues give rise to the appearance of different types of cancer, including cancer of the colon and skin, and leukaemia. The study has been undertaken in the Cell and Development Biology Laboratory headed by ICREA Research Professor Marco Milán, at IRB Barcelona, and has been released in and advanced online format by the EMBO Journal. The researchers have shown that the Notch and Wnt/Wingless signalling pathways exert control over the cell division machinery through two gene effectors, the proto-oncogene 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. “All the components were already known but we have clarified the order in the signalling cascade and the interaction between the molecular elements that regulate proliferation for the correct development of the wing”, explained Dr. Héctor Herranz, first author of the article. “Diseases like cancer cannot be understood without taking into account how the distinct molecular elements are integrated,” Prof. Milán said. 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 when mutations arise tumours appear. The fruit fly wing is a vital experimental model to find future biomedical applications. Prof. Milán goes on to say that “...this finding could provide clues about how to repress the cell proliferation signals in cancer”. The context is relevant 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 tumour suppressor while Wnt/Wingless acts as an oncogene, that is, by cancelling the action of Notch it allows the cell division machinery to operate,” Prof. Milán explains. 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 “tumour 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 signalling pathways work and that knowledge about the underlying regulatory elements is crucial to understand how a certain function is performed”, explains Dr. Herranz. According to Prof. Milán, diseases like cancer cannot be understood without taking into account how the distinct elements are integrated: that is to say, crosstalk between neighbouring 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”, he concludes. Reference: 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, advance online publication 1 May 2008; doi: 10.1038/emboj.2008.84 ......... ZenMaster

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