The complexity of brain wiring and connectivity remains one of the biggest mysteries in biology, and is of broad medical interest.
The extraordinary complexity of the cellular environment confronting cells in the central nervous system (10E10 neurons, 10E15 synapses) makes it a daunting task to conceptualize on a molecular level how specific synapses are selected or maintained. The problem of neural wiring specificity and its molecular control is particularly pertinent in the area of regenerative medicine. In this rapidly growing biomedical field, the aim is to induce or control the production of specialized differentiated neurons from stem cells, in order to allow for the replacement of damaged or lost adult neurons. However, there have been very few in vivo examples of successful specific neuronal cell differentiation described, and there can be little doubt that a large amount of crucial knowledge is missing in order to make the enterprise of using stem cells for circuit repair feasible. Furthermore, even for neuronal circuits that have been characterized extensively by sophisticated electrophysiological methods, our knowledge of the cellular components and their molecular identity is still remarkably poor. In addition to the medical relevance, understanding molecular mechanisms of neuronal specificity will not only be of value for therapeutic purposes, but will also give insight into fascinating questions regarding the evolution of neuronal circuits, and will likely shed light on the basis of and differences in cognitive abilities or personality traits in humans.
Research at the Neuronal Wiring Lab is focused on studying the molecular mechanisms of neuronal wiring and the specificity of molecular recognition processes mediated by membrane receptors. My lab has been using a combination of genetic, molecular, biochemical and structural methods to address the question of membrane receptor diversity and specificity. In particular, we have been studying how alternative splicing contributes to increasing protein diversity and how this is utilized for fine-tuning of axon guidance, axon/dendrite branching, and synaptic target choice within the Central Nervous System (CNS). Furthermore, we are comparing the molecular basis of recognition specificity of Ig-receptors in neuronal wiring, as well as immune responses.
Neuronal wiring and synaptic specificity
We are investigating the function of the Ig-domain containing neuronal receptor “Dscam”, a protein that is closely related to the human Down syndrome cell adhesion molecule (DSCAM). The Drosophila Dscam gene is highly complex. Through alternative splicing, up to 38,016 protein isoforms can be formed (Schmucker et al., 2000). All Dscam isoforms share the same overall molecular architecture but differ primarily in three distinct Ig-domains (Ig2, Ig3 & Ig7). Biochemical studies have shown that Dscam receptors can bind each other in a homophilic fashion. Remarkably, this homophilic binding is isoform-specific, suggesting the existence of an enormous binding specificity enabling the formation of potentially 19,000 different dimers. Functionally, Dscam has been shown to play an important role for the accurate connectivity of axons as well as complex dendrite morphogenesis.
Dscam in dendrites
Our genetic analysis of dendrite morphogenesis suggests that the homophilic binding specificity of Dscam isoforms is required in vivo and enables a “self” or “non-self” recognition in neurons.
Dscam in axons
Dscam and the specificity of isoforms is also involved in a number of axonal wiring processes and the selection of spatially distinct synapses. For example, reduction of the isoform diversity strongly impairs the precision of axonal growth and the synaptic connections of mechanosensory neurons within the CNS.
Dscam in the innate immune system
Dscam isoforms exhibit not only homophilic but also heterophilic binding specificity. We have discovered that the hypervariable neuronal receptor Dscam is also expressed in the immune system of flies, and that immune-competent cells have the potential to express more than 18,000 different isoforms. Our findings suggest an unsuspected molecular complexity of the innate immune system, raising the possibility of a molecular system for ”adaptive” immune responses in insects. It also emphasizes the notion that molecular recognition in the immune system and nervous system rely on shared or similar mechanisms and molecules.
Two future research goals are of particular interest
The group will expand their work on the wiring of the fly (Drosophila) nervous system and on mechanistically dissecting Dscam function and specificity. As a second goal, they will investigate how some of the molecular models can be extended to study the molecular diversity of neuronal receptors and the control of circuitry formation in the vertebrate nervous systems, using the new genetic model system Xenopus tropicalis.