| Project Detail |
Neurodevelopmental disorder is an umbrella term for a group of disorders that have their onset in childhood or adolescence. Despite the variability of symptoms, a common denominator are limited cognitive abilities and learning difficulties. Hence, neural circuit formation and function are negatively affected but the actual changes in neuronal wiring and network function are poorly understood. Based on genome-wide association studies and analysis of family pedigrees, a plethora of genes have been linked to neurodevelopmental disorders. For most of them the molecular mechanisms and their role in disease pathology is not known. Maybe not surprisingly, genes related to axon guidance are overrepresented among the genes associated with neurodevelopmental disorders. Based on our expertise, we propose to study the role of candidate genes and regulatory mechanisms in neural circuit formation, with a focus on axon guidance and cell migration. We will concentrate on commissural axon guidance in the spinal cord, the cerebellum, and the innervation of the hindlimb as a model for circuit formation in the peripheral nervous system. Obviously, commissural axon guidance in the spinal cord is not per se contributing to the cognitive problems associated with neurodevelopmental disorders, but it is one of the best models to study molecular mechanisms and the cooperation between signaling pathways. As molecular mechanisms of neural circuit formation are conserved throughout the nervous system, results can be transferred to other areas of the nervous system, such as the cerebellum, and tested for their contribution more efficiently. The cerebellum is a part of the CNS that is affected in autism spectrum disorder and ciliopathies. However, neural circuit formation in the cerebellum is poorly understood at the molecular level. Similarly, there are reports by parents and pediatricians that affected children respond differently to touch or other sensory stimuli than non-affected siblings, suggesting that neural circuits of the peripheral nervous system may also be aberrantly wired. Our research will focus on (1) the regulation of signaling during axonal navigation of choice points. How is the expression of guidance molecules and receptors precisely regulated to allow for smooth arrival and departure of an axon at the intermediate target? What are the mechanisms of temporal regulation of events during axonal navigation? (2) How is signal transfer between axons and target cells regulated in space and time? Do the mechanisms identified for axonal pathfinding in the spinal cord apply to the cerebellum? In particular, are the typical features of aberrant cerebellar peduncle formation, the hallmark of a subset of ciliopathies, caused by the same molecular mechanisms that cause deficits in commissural axon guidance at the spinal cord midline? (3) How do the genes associated with ciliopathies affect neural circuit formation? The primary cilium is well known for its role in cell differentiation but so far a role in axon guidance is still less clear. For all these studies, we will use in vivo and ex vivo protocols that have been established in the lab and have been published. For our studies, we will use primarily in vivo and ex vivo studies in chicken embryos, a system that allows for precise temporal and spatial control of gene function. |
