Neurobiologie moléculaire

Colloque organisé par Fotis Kafatos et Spyros Artavanis-Tsakonas du 16 au 22 juin 1991

Participants

Spyros Artavanis-Tsakonas (Yale University, USA), Heinrich Betz (ZMBH, Heidelberg, Germany), Sarah Bray (Cambridge University, UK), Linda Buck (Columbia University, USA), Pietro de Camilli (Yale University), Alberto Ferrus (University of Madrid, Spain), Correy S. Goodman (Berkeley University, USA), Martin Heisenberg (University of Wurzburg, Germany), Wieland B. Huttner (EMBL, Heidelberg, Germany), Reinhard Jahn (Max-Planck-Institute, Martinsried, Germany), Fotis C. Kafatos (Harvard University and Heraklion), Eric R. Kandel (Howard Hughes Medical Institute, USA), Bambos Kyriacou (Leicester University, UK), Alain Prochiantz (ENS Paris, France), Gerald Rubin (Berkeley University, USA), Elena V. Savvateeva (St-Petersburg University, Russia), Richard H. Scheller (Stanford University, USA), Hans Thoenen (Max-Planck-Institute, Martinsried, Germany), Benjamin Lewin (“Cell”, Cambridge, Massachusetts)

Introduction

Au cours des dernières années, le domaine dont la croissance a été la plus rapide dans les sciences biologiques est celui de la neurobiologie. Malgré les problèmes intrinsèquement posés par la complexité du système nerveux, les nouvelles méthodologies offertes par la biologie moléculaire ont suscité l’espoir qu’au moins certains aspects fonctionnels du système nerveux peuvent être finalement abordés au niveau moléculaire. Pourtant, le mariage de la neurobiologie classique et moléculaire est à un état embryonnaire et ne peut se réaliser que par un dialogue approfondi et ouvert entre ceux qui ont plutôt recours aux approches classiques et ceux qui utilisent essentiellement des outils moléculaires.

Compte-rendu (en anglais)

It is not unfair to say that in the past few years, the most rapidly growing field in the biological sciences is neurobiology. In spite of problems inherently posed by the complexity of the nervous System, the new methodologies offered by molecular biology have prompted the hope that, at least, some functional aspects of the nervous System can be finally addressed at the molecular level. Yet, the marriage of classical and molecular neurobiology is at an embryonic state and can only be realized by a thorough and open dialogue between those using classical approaches and those using primarily molecular tools.

Given the complexity of the nervous system the choice of relatively simple experimental models in which general principles can be pursued is of crucial importance. On the other hand, the fact that basic biological mechanisms transcend species barriers means that what is true for a fly is often true for mammals, including man. Several papers in the meeting emphasized the usefulness of the fruit fly Drosophila melanogaster as an exceptional experimental system. The genetic analysis that can be pursued in the fruit fly provides an extraordinarily powerful tool to dissect the molecular and genetic components important for neural function. However most of the progress made to date around the fundamental problem of synaptic transmission, are easily purified in quantities which allow biochemical analysis. The relevance of invertebrate experimental systems in higher order neurobiological problems, became quite evident during the colloquium. For example, in the sea snail Aplysia, certain behavioral responses which in mammals may involve a prohibitively large number of neurons, involve only a small number of well-defined neurons. In addition, it was shown that the genetic manipulation of flies can also provide significant insights into the molecular and genetic basis of particular behaviors.

The development of the nervous system in Drosophila was covered extensively (Rubin, Goodman, Bray and Artavanis-Tsakonas). In the past few years, substantial information has been gathered regarding how an undifferentiated cell chooses a neuronal developmental pathway, and many of the genes responsible for controlling cell fates choices in the nervous system have been identified. The cornerstone of cell fate choices in the early differentiation of the nervous system is cell communication. The molecular studies carried out so far lead to the identification of specific molecular components of cell fate controlling, cell interaction mechanisms. The power of genetic analysis in identifying interacting components of a given biochemical pathway has become obvious. The papers by Rubin and Artavanis-Tsakonas describing developmental events mediated by the surface receptors “sevenless” and Notch, have provided vivid examples of how fruitful genetic interaction screens can be in dissecting complex cell interaction mechanisms. Interestingly, it seems that the interaction mechanisms relevant for controlling the choice of a cell to follow neural development are not only operative in the nervous system, but are generally applicable to a broad spectrum of tissues. Moreover, comparative studies have demonstrated the astonishing conservation of these general mechanisms from flies to humans.

Thoenen described the latest work on neuronal growth factors, the small soluble molecules known to be involved in the growth and differentiation of neurons and Prochiantz provided some provocative results involving homeobox proteins in the control of neuronal shape. Once a cell has differentiated into a neuron, axonal connections have to be made. Axons sprout and grow over large distances in order to make the proper neuronal connections. This process is done with exquisite precision. While it is widely accepted that the interplay between the extracellular environment and the surface of the growing axon is the key to the correct axon guidance, virtually nothing is known about the molecules involved in this process. The power of genetics is also coming of age in the analysis of axonal guidance. Goodman described the initial results from his laboratory involving a genetic saturation screen designed to identify genes capable of influencing axonal growth and differentiation. The goal is to mutate every single gene in the genome and observe if any mutation affects the properties of axon growth.

Several papers (De Camilli, Betz, Huttner, Jahn) were devoted discussing the progress made elucidating the cell biology of synapses. Neurons are known to secret a cocktail of neuro-transmitters at synapses via two classes of organelles, synaptic vesicles and large dense core vesicles. The former store and secret non-peptide neurotransmitters and are involved in the fast point-to-point signaling typical of the nervous system — the latter store peptide neurotransmitters and are primarily involved in modulatory signaling. De Camilli reported the progress made in the elucidation of the biogenesis of the two organelles. Betz, Huttner and Jahn focused on the advancements in the characterization of molecular components of the membranes of synaptic vesicles. Synaptic vesicles undergo exo-endocytotic recycling in nerve terminals when they can be reloaded locally with neurotransmitters. Thus, their membranes must contain all the information required for the various steps of this cycle including docking and fusion to the presynaptic plasmalemma and vesicle formation of synaptic vesicle formation by selective budding. It is hoped that the elucidation of the structure and function of synaptic vesicle membranes may be relevant, not only to the understanding of presynaptic function, but also of vesicular traffic in general. The structure, properties and putative function of newly characterized synaptic vesicle proteins (including synaptotagmin, synaptoporin, rab3, and synaptobrevin) was discussed. New assays for the detection of synaptic vesicle exocytosis in cultured neurons based on the immunological detection of surface-exposed lumenal epitopes of synaptic vesicles were described. Putative molecular mechanisms involved in the docking of synaptic vesicle proteins to the presynaptic plasmalemma were illustrated. Finally, the relationship of synaptic vesicles, which were formerly thought to by neuron-specific organelles, to organelles of other cells was discussed. Organelles closely related to synaptic vesicles, both in the structure and in the function, are present in endocrine cells. In addition, synaptic vesicles appear to be more distantly related to organelles of the receptor-mediated recycling pathway expressed by all cells.

Scheller addressed the mechanisms involved in the recognition of pre- and post-synaptic structures. His paper was primarily focused on the structure and properties of agrin, an extracellular molecule which is thought to play a key role in this recognition.

Buck described the application of the newly developed “PCR” technology in the analysis of the molecular basis of odor discrimination. She was able to detect a new class of olfactory epithelium specific molecules which may define a hitherto unknown family of olfactory receptors. Kyriakou on the other hand, presented the latest on the molecular biology of circadian rhythms.

One of the most challenging problems of neurobiology today is the molecular and cellular basis of memory. Once again, simple experimental systems are proving to be invaluable. Kandel discussed how the analysis of the sea snail Aplysia continues to provide important dues in the study of the molecular basis of long term memory while Heisenberg has described his approach to identify Drosophila mutations affecting such higher order behaviors. Finally, Ferrus and Savvateeva discussed some aspects of the involvement of respectively cyclic AMP and Potassium channels in learning.

As Kafatos pointed out in his final remarks, this was a very successful colloquium which not only provided an opportunity to discuss the latest in a very rapidly advancing field but, most importantly, brought together a group of scientists representing diverse aspects of neuroscience’s providing a unique opportunity to explore future directions in a way that does not usually take place in more conventional meetings.

Spyros Artavanis-Tsakonas

Communications

• Spyros Artavanis-Tsakonas: Cell interactions and neuroblast segregation in Drosophila
• Heinrich Betz: Homology, analogy and diversity of synaptic membrane proteins
• Sarah Bray: Drosophila neuronal gene expression
• Linda Buck: A molecular basis for odor discrimination
• Pietro de Camilli: Mechanisms of secretion from neurons
• Alberto Ferrus: Genetic links between learning and development of the CNS via K+channels and their modulators
• Correy S. Goodman: Pathway and target recognition in Drosophila
• Martin Heisenberg: Drosophila Neurogenetics
• Wieland B. Huttner: Large dense core vesicle biogenesis
• Reinhard Jahn: New approaches to study the cell biology of the nerve terminal
• Fotis C. Kafatos: Concluding remarks
• Eric R. Kandel: Molecular approaches to System Memory in Aplysia
• Bambos Kyriacou: Molecular analysis of behaviour
• Alain Prochiantz: Neuronal shape
• Gerald Rubin: Drosophila eye development
• Elena V. Savvateeva: Genetic dissection of CAMP System for study of learning
• Richard H. Scheller: Synapse Development
• Hans Thoenen: NGF gene family: new molecules, new functions, new perspectives