Fly-ing Neurobiology. A Brief History of Nervous System Studies in Flies

The common fruit fly, Drosophila melanogaster, has been (and continues to be) a long-time favorite model organism for the study of the nervous system. Early in the 1960s, Seymour Benzer pioneered “neurogenetics” in Drosophila, a new methodological approach, arguing that neural genes could be uncovered by behavioral and/or physiological screens, and that, most importantly, single genes could make a difference and be uncovered by virtue of mutant phenotypes. His lab then went on to discover the first circadian rhythm genes (research distinguished with a Nobel prize in Medicine of Physiology to Jeffrey C. Hall, Michael Rosbash, Michael W. Young; see bloc in p. 226), the first genes isolated that are required for courtship, a research avenue that led to further insight into neural architecture, the sex determination molecular cascade, and the first memory genes, all work that has continued unabated to this day.

Yet, even before Seymour Benzer, in the 1940s, the basis of the formation of the nervous system were being set up and firstly studied by John Poulson at Yale University. He uncovered an embryonic lethal mutation that gave rise to aberrant brain tissue
—very big brains—a phenotype occurring in mutant alleles of the Notch (a genetic marker) locus. In effect, we now know that these genes (there are several of them appropriately termed neurogenic genes), are crucial for the division of skin cell precursors (epidermoblasts) and neural precursors (neuroblasts) in the ventral surface of the developing embryos. The action of the neurogenic genes is to limit the number of cells that become precursors of the nervous system, such that their lack of function lead to excessive numbers of neural precursors, and, therefore, to very big (but non-functional) brains. Their action is opposed by the pro-neural genes, that promote nervous system destinies. The work was continued by many labs, amongst which those of Spyridon Artavanis-Tsakonas at Yale, and then, at Harvard, and José Campos-Ortega, in Cologne, Germany, became famous. They regularly got together in the Greek island of Crete to discuss their progress (and this gave rise to a biannual meeting that continues to this day about Drosophila development). This work was aided by the embryonic mutant screens performed by the Christianne Nüsslein-Volhard and Eric Wieschaus groups, that isolated mutations in most of the critical loci for embryonic development, a work also distinguished with a Nobel prize. These genes are evolutionarily conserved and are used in the formation of nervous systems in many species, including vertebrates and humans. In fact, they uncovered a basic signal transduction mechanism present in animals. 

The next big development came with the systematic study of eye formation and function, and then, of other sensory modalities like olfaction. The labs of Jerry Rubin in California and of Seymour Benzer tackled the formation of the R7, a type of photoreceptor in the eye of the adult fly. The retina has always been considered a part of the central nervous system “outside of the brain”, and so, in studying the development of this cell type, they uncovered a general cellular signaling pathway present in all animals, again. This work continued in many labs, amongst which those of Ernst Hafen, in Zürich, Switzerland, and Utpal Banerjee, in California, made great contributions (figure 1.)

Figure 1. Sensory structures in the head of Drosophila sp.

The adult fly head is equipped with a wide array of sensory structures. The micrograph is an image of an adult fly head obtained with a scanning electron microscope. The light blue arrow points to the compound eyes (so-called because they are made of small eyes put together, each constituent eye is called an ommatidia, and they look like small spheres), the dark blue arrow points to the eyes in the dorsal side of the head, the ocelli, also visual organs, made up of three separated single ommatidia. The red arrow points to the antennal third segment, the main olfactory organ; the second segment, above, is the main auditory organ, or ears. The orange arrow points to the maxillary palps, a second olfactory organ. Finally, the green arrow points to the labellum, a gustatory organ. In addition, the “hairs” or chaetae throughout the head are innervated and are mechanosensory organs.

Olfaction studies were pioneered by Obaid Siddiqi in India, and later by John Carlson at Yale. Importantly, the olfactory receptor genes were identified in flies by both the Carlson group at Yale and the Richard Axel group at Columbia, New York (Axel had already cloned the vertebrate receptor genes in rats, a work that also received a Nobel prize). The Carlson group then went on to identify the gustatory receptors. All these genes code membrane proteins of an evolutionary conserved class, the so-called G-PCRs, an acronym for “G-protein coupled receptors”, proteins that sit on cellular membranes and communicate to the interior of the cell by means of signaling pathways that use intracellular G-proteins. Members of this gene family are required throughout the nervous system, as neurotransmitter and neuromodulator receptors, sensory receptors (as seen above).

The next big question in neurosciences was to understand the detailed logic of coding and processing of information in the brain, and for that, the complete “wiring diagram” of the nervous system is required. And indeed, the flies have come again as the organism of choice for this endeavor. Recently, both the connectome (that is, the map of all the neurons and glial cells in the brain, and the connections between them) has been published, both for the larval brain (first) and for the adult brain. This means in a new era in Neurosciences is rising, since for the first time we have the complete blueprint of a complex nervous system (the fly adult brain has about 140,000 neurons) and can now ask questions of how information travels and is treated. This, coupled with the development of techniques to silence or alter behaviors of individual neuron(s) in vivo, in the living animal, brings unparalleled power to nervous system studies in the fly. We are just beginning to reap the benefits of such a new bonanza.

Personally, my research has always gravitated around the idea that flies, as a unique model organism, are poised to unlock general principles of nervous tissue formation and function. During my graduate studies I characterized several genes that were known to be required for vision, showing that they were also required for olfaction, and isolating fly stocks that had genes expressed in olfactory tissue. Later, I embarked on studies of genes required for neural information processing, signal transduction (cell signaling) during development and function of the brain, and, in the neural consequences of deficits in insulin signaling. Of note, in flies, the insulin producing cells are neurons located within the fly central brain.

FOR THE FIRST TIME WE HAVE THE COMPLETE BLUEPRINT OF A COMPLEX NERVOUS SYSTEM AND CAN ASK QUESTIONS OF HOW INFORMATION TRAVELS AND IS TREATED

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