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Cellular and molecular mechanisms of nervous system development and lifelong maintenance

We study how nervous systems are assembled and how they are subsequently protected throughout life. For this we use the powerful model system C. elegans that has been critical to unravel fundamental biological processes of neuronal function and development, and aging. We take a multidisciplinary approach that includes genetics, molecular biology, cell biology, biochemistry, transcriptomics and proteomics. Thanks to our collaborations with other labs, we join forces and validate our findings in other systems.

 

We focus on two major questions:

1) How do neural circuits develop?

Migrating neurons and developing axons are guided as they navigate through complex environments to reach their targets. These directed migrations are essential to ensure the proper wiring and function of the nervous system. Much research over the past two decades has led to the identification of guidance cues and receptors that instruct guidance decisions. Remarkably, there is a small set of guidance cues and receptors compared to a large number of different types of neurons and the myriad contexts in which they develop. Such paucity of guidance molecules suggests that there must be regulatory mechanisms that diversify the actions of these guidance cues, in order to meet the challenges of constructing an immensely complex nervous system. However, the mechanisms by which guidance signals are orchestrated are still poorly understood. One of the mechanisms that we are currently studying involves heparan sulfate proteoglycans and their roles in regulating the number of cellular extensions that migrating cells develop. Answering these questions is central to our understanding of how neurons and growing neurites are guided not only during development to assemble neural circuits, but also in regeneration after injury.

2) How is the architecture of the nervous system maintained lifelong?

After the initial assembly of the nervous system during embryogenesis, neural circuits need to persist in the face of subsequent maturation and the physical stresses exerted by growth, body movements, injury, and aging. Little is known about the mechanisms that serve the long-term maintenance of the nervous system architecture and connectivity. It has long been assumed that neural circuits developed earlier in development simply grow in size and that the neurons retain their precise positions and connections by the mere existence of extracellular matrices that keep them in place. However, our research and that of others has demonstrated that there are molecular mechanisms dedicated to the active maintenance of the nervous system. Through our research, we have identified several proteins with roles dedicated to long-term nervous system protection, including a member of the conserved L1CAM family, SAX-7, and extracellular matrix molecules that actively contribute to the lifelong maintenance of neuronal structure and function. This research may shed light on the molecular bases of neurodegenerative diseases and other neurological disorders. As such, whereas the age-dependency of neurodegenerative diseases and cognitive decline are well-known conditions in human life, the mechanisms by which age triggers these conditions are largely unknown. Our long-term goal is to uncover all determinants of neuronal maintenance and elucidate their roles in protecting the nervous system throughout life, from maturation in juveniles to aging adults.

Given that the development and function of the C. elegans nervous system has a high degree of evolutionary conservation with the mammalian brain, we expect that our research will ultimately provide crucial information to develop more sensitive diagnostic approaches and to ameliorate the consequences of neurodevelopmental and neurodegenerative conditions.

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