Zebrafish have an amazing capacity for central nervous system (CNS) regeneration. They regain function after complete lesions of the spinal cord or the optic nerve. Such lesions in mammals are not repaired and functions are permanently lost.

    How can zebrafish replace lost neurons from adult stem cells?

    How are severed axonal connections repaired?

    How are these processes related to developmental neurogenesis and axonal pathfinding?

To address these questions we are focusing on two important cell types, retinal ganglion cells, which convey all visual information form the eye to the brain, and spinal motor neurons, which control muscle contraction during swimming:

Retinal ganglion cell axons navigate to their targets guided by a variety of molecules. We have found that molecules of the extracellular matrix are essential for pathfinding of developing as well as regenerating axons to their termination areas in zebrafish. We are continuing to investigate which molecules are needed for correct guidance and termination of developing and regenerating retinal ganglion cells using a variety of techniques, such as gene knock down, mutant analysis and expression profiling.

Motor neurons are important target cells for axons descending from the brainstem that control swimming movements. We have shown that regeneration of descending axons is necessary for functional recovery after a spinal lesion and are now investigating the signals that lead to the (re-)generation of motor neurons. We have found that in embryonic motor neurons, transcriptional co-factors control expression of specific cell recognition molecules, such as plexins and neuropilins, which in turn are necessary for pathfinding of embryonic motor axons. We are now using small molecule screens and expression profiling on cDNA microarrays to discover new factors that are important for motor neuron differentiation, both during development and adult regeneration.

By analysing development and regeneration of important cell types in the zebrafish we hope to gain insight into fundamental developmental and regenerative mechanisms in the CNS, and to ultimately increase our understanding of human conditions, such as spinal cord injury and motor neuron disease.

In summary, my research contributes to a better understanding of the factors allowing generation of neurons and axonal pathfinding in the CNS during development and regeneration. I use the zebrafish model to find fundamental mechanisms in vertebrates with clear implications for stem cell biology and research into CNS injury and neurodegenerative diseases.