Navigation auf uzh.ch
Navigation auf uzh.ch
What happens to the brain when primary cilia, our cells' antennae, don't function?
Primary cilia act as the antennas of our cells, sensing environmental cues to guide cell behavior. When cilia don’t function, patients develop brain malformations and/or display developmental and learning disorders. This indicates that cilia are important for formation and function of the brain. In this project we are using zebrafish and human induced pluripotent stem cell models to study the role of cilia in the brain.
Neural circuits are the basis for learning and memory. We aim to elucidate the role of primary cilia, sensory organelles that serve as antennae of cells, in the establishment and regulation of neural circuits using zebrafish and iPSC-derived models.
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. 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 (Noble et al., 2024).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.
In parallel to the work in zebrafish, we are analysing the role of primary cilia in neural circuit development using human induced pluripotent stem cell (hiPSC)-derived cortical neurons. In a first publication in collaboration with the AdaBD iPSC platform, we have systematically assessed primary cilia number and length in a variety of iPSC-derived neuronal models. This has identified the presence of primary cilia not only on the cell soma but also on neurites. Using live imaging with fluorescently marked primary cilia, we are now investigating this highly dynamic behavior of cilia which has not been described so far in any model to our knowledge. Further, we will evaluate the consequences of perturbations through knock-out of ciliopathy- and autism-associated genes. Finally, we will investigate the influence of primary cilia on synapses using transcriptomics, super-resolution expansion microscopy and electrophysiology.
Our findings will contribute to a better understanding of the role of primary cilia in establishment and regulation of neural circuits and help elucidate the pathomechanisms underlying ciliopathies such as Joubert Syndrome and developmental disorders such as autism-spectrum-disorders.
Principal investigators: Ruxandra Bachmann-Gagescu, Esther Stoeckli
PhD students: Elkhan Yusifov (until 2024), Alexandra Noble, Thomas Lobriglio
Platforms: HDDS, mesoSPIM
Yusifov E, Schaettin M, Dumoulin A, Bachmann-Gagescu R, Stoeckli E (2025)The primary cilium gene CPLANE1 is required for peripheral nervous system development
Developmental Biology
Noble A, Masek M, Hofmann C, Cuoco A, Rusterholz T, Özkoc H, Greter N, Phelps IG, 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 systemBiologyOpen
Underlined: AdaBD researchers
