Oh what a birthday! Frontiers in developmental neuroscience
“Round birthdays” aren’t always a cause for personal celebration, but when taken as an opportunity to take stock of a field – and to appreciate a scientist’s contributions to it – they can be glorious affairs. Thus was the case on July 10, when the MDC celebrated Carmen Birchmeier’s 60th birthday with a series of talks by leading international scientists who count among her friends, colleagues, and collaborators over the course of many years. Starting with a keynote lecture by Tom Jessell and culminating with a piano recital by BIMSB co-ordinator and MDC group leader Nikolaus Rajewsky, it was an event to remember.
The MDC's director, Thomas Sommer, opened the day by listing many of the topics that have occupied Carmen throughout her career – from early work on mRNAs and histone genes to oncogenes, genetic studies of tyrosine kinases, and her current work on developmental neurobiology, stem cells and muscle. Thomas was a junior group leader at the MDC when she arrived in Berlin-Buch in 1994 and shared a few personal anecdotes; if you weren’t there, come to the next event, in ten years, and maybe you’ll hear them then.
Many of the projects described in the talks would have seemed utterly fantastic a decade ago, had a similar event been held on Carmen’s last round birthday. One recurring theme was integration: attempts to weave studies of molecular and cellular mechanisms in the nervous system into an understanding of higher-order functions related to behavior.
Tom Jessell of Columbia University (NY) set the tone by describing ongoing work in his laboratory to understand the functional organization of populations of cells in the spinal cord. How is the central nervous system constructed to permit animals to control “skilled” movements – such as grasping behavior on the part of mice that have been trained to reach for a food pellet? These functions must depend on feedback between motor neurons and sensory neurons, which permit purposeful movement and its success. Studies by Jessell’s lab and others suggest that the feedback is managed by a circuit-like network involving these two types of cells and a third – interneurons – which plays a crucial role in their coordination. But the bewildering array of interneuronal subtypes – at least hundreds – has made it incredibly difficult to understand their functions.
Jessell says that interneurons shape behavioral output through their inhibitory effects, dampening transmission between the other types of nerves either presynaptically or post-synaptically. Most of these inhibitory contacts are wired into the system post-synaptically, but it has been unclear which type of inhibition has the strongest effect on skilled movements. The laboratory used an elegant method to eliminate presynaptic inhibitory neurons and to study the functional consequences. While there are fewer presynaptic connections, they have a large impact on trained motor behavior.
In a later talk Silvia Arber, of the Biozentrum and FMI Basel, followed up on the theme of the connectivity of cells in the spinal cord and brainstem and their effects on behavioral circuitry. A major project has been to use tools derived from the rabies virus to map the connections between precise populations of cells in the mouse brainstem and direct motor nerve targets. In projects partly carried out in collaboration with Jessell’s group, her lab has also dissected the contributions of particular cells to the pellet-grasping task in mice. Her group was able to demonstrate the specific effects of interfering with this communication route: mice still reached for the pellet, but they were unable to grasp it. This suggests that particular populations of brainstem neurons were responsible for “skilled” forelimb movements.
Late in the afternoon David Ginty, of Harvard Medical School, gave another talk on circuits in the nervous system. Recent work by his lab has aimed to reveal the “ultrastructural” basis by which low-threshold mechanoreceptors (or LTMRs) distinguish different types of sensations. These nerves extend from the spine to the surface of the skin, where they assume different configurations around the “stems” of hair follicles. Ginty and his colleagues have demonstrated that nerves which are highly sensitive to gentle strokes (called A-beta “Field” LTMRs) have circumferential endings – they encircle the base of the follicles. Other classes of LTMRs have different configurations at their tips that make them insensitive to stroking, but they respond to other types of stimulation, such as puffs of air. The group has combined genetic studies with light and electron microscopy to image these structures and correlate nerve architecture with functions. The work is helping to explain cases of touch hypersensitivity found in mutant animals and some cases of humans affected by autism, Fragile X syndrome, or other conditions.
Other aspects of neuronal structure were covered in a report by Benjamin Podbilewicz of the Technion (Haifa, Israel). Podbilewicz’s lab has extended findings about cell-cell fusion in the skin of the worm C. elegans to the “menhorah”-like structure of nerve cells. The growing tips of these nerves undergo a process of pruning – in which early multiple extensions fuse – to assume a shape where a central process branches off into distinct sections. The scientists have established that a molecule called eff-1, which regulates cell fusion in the worm, is required so that growing tips will merge into this regular structure. Disrupting the protein leads to a chaotic structure with excessive branching and nerves that are unable to assume the morphology they need to carry out their functions.
Nils Brose, of the MPI for Experimental Medicine in Göttingen, reported on electron microscope studies combined with genetic work that aims to clarify the means by which presynaptic vesicles associate and fuse with the membranes of cells. The lab’s studies have helped clarify the roles of molecules such as SNARES and “priming” proteins in targeting vesicles to membranes. Quantitative studies based on electron microscopy are revealing the roles of particular factors in priming vesicles, attaching them to membranes, and creating the protein complexes required for synaptic function. Some of the disruptions the group has observed suggest that particular mutations cause increases in the volume of synaptic vesicles due to their aberrant uptake – possibly due to recycling defects – and are helping to revise views of the way assemblies of SNARES and other proteins manage the steps involved in synaptic structure.
Processes that take place at neuronal membranes are also thought to be crucial to the development of Alzheimer’s disease, in which a protein called APP is cleaved by enzymes to produce a molecular fragment that leads to amyloid plaques. Christian Haass (DZNE and LMU München) talked about his lab’s work on an enzyme called beta-secretase (BACE-1), which is highly expressed in early postnatal development and is active at the membrane. BACE-1 may be a useful therapeutic target in attempting to prevent the formation of amyloids and the development of disease pathology. His work suggests that the protease has also other important roles, so side effects of drugs that affect its activity need to be considered.
Two speakers focused on topics related to neuronal stem cells and differentiation. François Guillemot of the Francis Crick Institute in London described work on such cells in adults. Several years ago researchers discovered stem cell niches the brain, which continue to produce neurons in the hippocampus and olafactory bulbs throughout an animal’s lifetime. Many questions remain about the biochemical signals that ensure the survival of these cells, maintain or end their quiescence, and finally prompt their development and integration into the structure of existing brain tissue. These processes are crucial to brain plasticity and are affected by both environmental factors and learning. Guillemot and his colleagues have helped clarify the role of a transcription factor called ASCL1, which helps govern the transition between quiescent and actively proliferating cells. The fate of a particular cell in the hippocampus seems to depend on a negotiation with a Bmp4 factor, which is known as a negative regulator of neural development, and active signals that have not yet been identified.
Rhona Mirsky of the University College London delivered an interesting report on developmental aspects of Schwann cells, which surround axons with myelin sheaths and suffer defects in a number of deadly neurodegenerative diseases. Mirsky reported on signals that transform the cells into Bungner cells, which are capable of repairing damage to the peripheral nervous system, but not the central nervous system. A well-known signal called c-Jun is strongly upregulated in the cells in response to injuries. After repairs, Bungner cells can reverse their development and become Schwann cells again. Without c-Jun, however, the repair response seems to be poor or non-existent and neurons have a poor survival rate. Bungner cells with active c-Jun seem to be more active, at least in early stages of repair. Mirsky says that the “textbook” account of repair following damage to the sheath mainly attributes the clearance of myelin fragments to immune cells, whereas her lab showed that Schwann cells are able to digest the debris themselves.
Gary Lewin was the only speaker from the MDC. He gave a fascinating report on recent work his lab has carried out in collaboration with Stefan Kempa’s group on the naked mole rat, a model organism he introduced to the institute several years ago. Over the past few years most of the lab’s work has focused on the mechanisms that make the animal insensitive to several types of pain. Recently the group has made a number of stunning discoveries about unusual metabolic processes that permit the naked mole rat to survive in environments with virtually no oxygen. He left the audience on the edge of their seats in anticipation of upcoming publications that hint at entirely new metabolic pathways in this unusual animal.
The last speaker of the day was Mike Wigler, of Cold Spring Harbor Laboratory (NY), in whose lab Carmen worked in the 1980s. He explained that her work had had a major influence on his lab’s direction. The talk covered a current project based on identifying mutations – frequently involving the amplification or loss of genomic regions and changes in copy numbers of genes – responsible for autism. The image he provided of this disease, or this cluster of common symptoms, was a reminder of the incredibly complexity of many of the questions scientists would like to answer regarding the nervous system. On the one hand it was a sobering message. On the other, it points to the fact that developmental neuroscience is a frontier that, in many ways, has only barely opened itself to the tools of modern science.
On that note, Nikolaus Rajewsky took the stage and gave perhaps the best possible example of the human nervous system at work – in the pursuit of music, art, and beauty.
What a birthday!
Featured Image: Benjamin Podbilewicz, Walter Birchmeier, and - guess who? - guest of honor Carmen Birchmeier. Photo: Michael Strehle, MDC
