ESR8

The role of Joubert syndrome-associated proteins in neuronal development

Joubert syndrome (JBTS) is a neuronal ciliopathy, characterized by a distinctive brain malformation known as the "molar tooth sign", as well as heterogenous other manifestations both in the brain and other organs. The common mechanism of disease in the brain remains unclear, but is suggested to be loss of neural signalling. We developed an in vitro model to investigate neuronal development, by differentiating hiPSCs into excitatory neurons (iNeurons) and forebrain organoids. ESR8 will use three selected JBTS patient-derived hiPSCs from ciliary protein modules that are differentially localized across the ciliary axoneme, as well as isogenic CRIPSR/Cas9-edited lines for neuronal network measurements using microelectrode arrays (MEAs). As iNeurons exhibit patterns of synchronized and rhythmic activity on MEAs, ESR8 will generate a developmental network MEA fingerprint that functionally describes the properties of the neural signalling circuits. Complemented with superresolution (STORM and CLEM, in collaboration with PO2-MPI-CBG) and live cell imaging of JBTS-associated markers, measurements of cilium formation/stability in organoids, and ciliary signalling assays, this will unveil critical information on the defects in neuronal development and signalling.

Partner: Radboud University Medical Centre Nijmegen, The Netherlands

Supervisor: dr N. Nadif Kasri