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One mold and many forms

Expression of the same gene in distinct tissues or at different moments has contributed to the biological diversity of the species

A merger of bat wing images (John Zook/University of Ohio) and hand (eduardo cesar) Appearances are misleading: hand and wing have the same genetic originA merger of bat wing images (John Zook/University of Ohio) and hand (eduardo cesar)

A person’s hand and a bat’s wing carry out such different functions that they seem to have different designs. But a closer look reveals similarities. The human hand and the bat’s wing are formed from the same number of bones, according to instructions of the same genes. During development, it is enough for one central gene of the hand to be more active than the front claw of a bat embryo to form a wing. The use of embryo development to understand how tiny changes in the same design created most of the planet’s biological diversity is the work of a field of biology called evo-devo, the result of a merger of the words evolution and development.  Evo-devo was the main topic of the 54th Brazilian Congress of Genetics, held in the city of Salvador, State of Bahia, last September.

Research studies presented during the event show that very often tiny differences at the moment or place where the gene is activated determines the origin of evolutionary novelties. “If your face differs from the face of the person besides you, this is because of the neural crest cells – therefore, it is wise to know something about them,” says the US’s Marianne Bronner-Fraser, from California Technology Institute/Caltech.

Neural crest cells arise when vertebrate animals- such as fish, amphibians, reptiles, birds and mammals – nervous systems’ begin to form. These cells migrate to the periphery of the embryo, where they give rise to the peripheral nervous system, the facial color of some animals, part of the facial bones and birds’ beaks. The small variations in this process make human faces differ one from the other. Marianne studies the genes that coordinate the formation and migration of these cells to answer a basic question: how one specific type of cell that had not existed appeared together with the vertebrates.

The first challenge was to describe the genes that regulate the embryonic development of the lamprey eel, a long, gelatinous-like fish that feeds on the blood of other fish. The lamprey eel is not very attractive looking, and represents the oldest vertebrate branch, which is why it is compared to other animals that provide information as to how this group arose. Marianne’s team investigated approximately 50 active genes in the lamprey eel’s embryo; in an article published in 2007 in Developmental Cell, the team showed that some of the most important genes to form an adult lamprey eel are similar to the genes that control the embryonic development of other vertebrates. In many cases, the main difference is that some genes that go into action at the initial development stage of these animals are activated at a later stage in the lamprey eel. The researcher showed that the initial part of the gene circuit that regulates development has existed for more than 500 million years.

To understand the origin of this circuit, Marianne compared the development of the lamprey eel with that of the amphioxus – existing representatives of the vertebrates’ ancestors which resemble small fish; however, amphioxus do not have a spinal column or a neural crest. Marianne investigated the genome of the amphioxus and found similar genes to the ones that regulate the formation of the neural crest in vertebrates, according to the article published this year in Genome Research. “The amphioxus has at least one copy of all the genes that exist in various copies in the vertebrates,” she says, suggesting that ancestral vertebrates already had the genes that were co-opted for a new function in these animals, which was to produce the neural crest.

Argentina’s Pablo Wappner, from the University of Buenos Aires, also investigates genes that carry out distinct functions in different organisms. He investigated how the respiratory system is formed in the drosophila. Unlike vertebrate animals, insects do not have a circulatory system and breathe through tracheas, subdivided tubes that take oxygen to several parts of the body and are formed according to the instructions of the same genes that build up the circulatory system in mammals. Wappner has shown why the tracheas of drosophilae and the blood vessels of mammals branch out when there is little oxygen, thus increasing efficiency in the transportation of oxygen to the tissues. In an article published in Methods in Enzymology in 2007, Wappner described the cascade of genes that is activated in the absence of oxygen in the branches leading to the trachea. He believes it is possible to apply what he has learned about drosophilae to the human circulatory system.

Physician José Xavier Neto, from the University of São Paulo’s Heart Institute/InCor, has made great progress in terms of understanding how the human heart is formed. The heart of a vertebrate animal has a unique architecture arranged in chambers: one chamber gets the blood and the other chamber contracts and sends the blood forward. In other animals, with the exception of mollusks, the blood vessels transport the blood by means of constricting the walls – a method whose weakness is that it creates movement in two directions, as if someone were squeezing a toothpaste tube in the middle. Xavier has shown that the forming of the chambers depends on retinoic acid levels in the embryo. “If we treat the embryo with high doses of retinoic acid, the heart turns into a big atrium; if we inhibit the production of the acid, only the ventricle develops.” Xavier has shown that during an embryo’s development, retinoic acid spreads out like a wave: it is first produced in the tail and slowly moves towards the head. As the heart is aligned with the body’s axis, in the beginning the enzymes that produce the compound are produced in the cells of the atrium. When the wave reaches the ventricles, their development has already been defined and no changes occur.

The researcher from InCor noticed that the retinoic acid wave also exists in amphibians, birds, mammals and fish, including lamprey eels. The amphioxus produces similar enzymes to the ones that produce retinoic acid, but the compound does not spread out like a wave. At medical conferences, Xavier has discussed the synthesis of his work. He collected all the data he had obtained thus far and suggests that the retinoic acid wave existed before the rise of vertebrates and the chamber-divided heart. The group is now investigating the genes that command the production of retinoic acid. Understanding how the heart develops may guide the diagnosis and treatment of congenital heart defects.

Matthias Gerberding/ Max Planck InstituteGenetic material dyed blue marks the different development stages of the crustacean embryoMatthias Gerberding/ Max Planck Institute

Another source of diversity is the expression of the genes that give rise to insects’ body segments – the same genes that determine the different segments of a mouse’s backbone. Like all other flies, drosophilae have a pair of wings and a pair of appendages called balancers. Biologist Nipam Patel, from the University of California at Berkeley, reported that when he silences the ultrabithorax gene (ubx), wings arise instead of balancers. With four wings, the fly resembles butterflies and bees, another indication that small changes generate diversity of forms. However, the development of wings has not been totally unraveled yet: in butterflies, Patel found major ubx activity in the back wings, but not in the front ones, which are bigger. Evolution seems to have resources to alternative mechanisms for the building of insect wings.

Patel is also investigating the function of the ubx gene in crustaceans, which have an uncommon diversity in terms of development and architecture. The hind part of these animals is comprised of several segments – each one of which can have legs, claws or a special mouthpart appendage called maxilliped. The researcher from Berkeley noticed that in shrimp from the Periclimenes class, the ubx gene only goes into action from the fourth segment onwards, where the legs begin. Patel developed a method to activate the gene in the first segments and reduce the gene expression in the hind segments. As a result, legs grew where the maxillipeds should have been and vice versa.

He is also investigating another symmetry-related issue: the differences between organisms’ right and left sides.  In human beings, the heart and the stomach lie more towards the left, while the liver lies more to the right. When this symmetry is flawed, the organs do not fit properly, usually resulting in a fatal condition. The Nodal is the gene that is responsible for this symmetry. Patel showed that this same gene determines the coiled architecture of snail shells; in some species, the shell coils to the left and in others to the right. If the Nodal is inhibited at the onset of development, the shell stretches and does not coil. But why is the gene expressed on only side of the body? Patel does not know the answer yet.

He is not the only researcher to be interested in drosophilae wings. Geneticist Blanche Bitner-Mathé, from the Federal University of Rio de Janeiro/UFRJ, studies the diversity in terms of size and shape of these flies’ wings. Unlike other specialists in evo-devo who studied embryology prior to studying genes, Blanche started off from a genetic evolution approach and is now searching for explanations on her discoveries. She raised drosophilae of the Drosophila melanogaster species under different temperatures (16,5˚ C and 22˚ C). From each generation, she selected the ten flies with the longest wings and ten flies with the most rounded wings. These flies would give rise to the next generation, always raised under the same temperatures. The research group from Rio de Janeiro noticed that the response to the selection varied according to the environment. At 22˚ C, at the end of 50 generations, the team had obtained long-winged flies and rounded-winged flies – a shape that is not seen in a colder temperature or in the wild. “The genome has the potential to create forms that do not necessarily exist,” summarizes the researcher, who is now investigating the rotund gene, whose name was coined because it generates more rounded wings when it is modified.

Blanche’s research work goes beyond evolution and development. “Our findings reinforce how important it is to study the interface between ecology, evolution and development,” she says, defining eco-evo-devo. In collaboration with the Insect Molecular Biology Laboratory of the Fundação Oswaldo Cruz foundation, the group noticed that  longer wings produce a sound that differs from the one produced by the rounded-wing flies – and that the females prefer the long-winged males. Success among females might help explain why drosophilae always have long wings when they are in the natural environment.

Klaus Hartfelder, from the Ribeirão Preto campus of the University of São Paulo/USP, is also concentrating on one species: he is trying to explain how the two larvae of genetically identical bees are separated into queen bee or worker bee.  He noticed that the genes linked to the metabolism of insulin are more active during the development of the worker bees than that of the queen bees, according to an article published in the Journal of Insect Physiology. This is what the researcher refers to as the bee paradox, because insulin promotes growth in other insects. In the case of bees, things seem to be different:  the queen bees are much bigger, but they have these genes that are silent during development.

Hartfelder also noticed that growth hormone levels are higher at the beginning of the development of the queen bee’s larvae. This hormone protects the ovaries from cell death, thus leading adult queen bees to have approximately two hundred ovule-producing structures, while the worker bees only have from 2 to 12 such structures in each ovary. Hartfelder’s group is now analyzing which are the more active genes in the ovaries of the queen bees and of the worker bees, to understand better how these two castes are formed.

What is the solution to this bee enigma? Hartfelder?s face lights up: “I don’t know!” Mysteries such as this one, which arouse curiosity from researchers, is what make eco-evo-devo currently one of the most celebrated categories in the field of biology.