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What happens to the zebrafish brain when genes associated with the neurodevelopmental disorder Joubert Syndrome are altered?
Joubert syndrome (JBTS) can cause neurological symptoms and developmental delay. In this project, we are studying how the brain develops in zebrafish with alterations in genes affected in people with JBTS. In a first publication, we show that JBTS genes affect the way brain cells behave in zebrafish, leading to changes in the way that they swim.
Neural circuits are the basis for learning and memory. The establishment of proper neural circuits depends on cellular signalling pathways, some of which are controlled by primary cilia, organelles that serve as antennae of cells. We aim to elucidate the role of primary cilia in the establishment of neural circuits, with a special focus on cerebellar circuits in zebrafish.
We have found that cerebellar neurons of zebrafish mutants for the ciliopathy genes cc2d2a and talpid3 have fewer primary cilia that are positive for the ciliary GTPase Arl13b at larval stages compared to wild type controls. However, this does not result in changes to cerebellar morphology. These mutants do however show a dysregulated expression of genes that may regulate neuronal function, including genes encoding voltage-gated ion channel subunits and neurotransmitter receptor subunits. Furthermore, cc2d2a mutants show abnormal swimming behaviours. Together, this indicates that primary cilia in the zebrafish may be required for neural circuit function rather than development. Future directions for this project could involve a more detailed analysis of neural circuit function using transgenic zebrafish lines expressing neuron-specific genetically encoded calcium indicators.
To complement our work in zebrafish, we are further analysing the role of primary cilia in neural circuit development using human induced pluripotent stem cell (hiPSC)-derived cortical neurons.
This project analyses neural circuit development in zebrafish using a combination of techniques, including advanced imaging techniques like mesoSPIM and data analysis using Dataspace, and therefore generates synergies between different groups and platforms.
Principal investigators: Ruxandra Bachmann, Esther Stoeckli
PhD student: Alexandra Noble
Platforms: HDDA, mesoSPIM
Noble A, Masek M, Hofmann C, Cuoco A, Rusterholz T, Özkoc H, Greter N, Vladimirov N, Kollmorgen S, Stoeckli E, Bachmann-Gagescu R (2024)
Shared and unique consequences of Joubert-gene loss-of-function on the zebrafish central nervous systembioRxiv
Underlined: AdaBD researchers
