Anatomical Society Summer Meeting, Oxford: 14th‐16th July 2025

Primary cilia-small protrusions from the cell surface-act as the cell's antennae and control cell-cell signalling.Ciliary dysfunction can cause severe neurological symptoms, most commonly intellectual disability (ID) and autism spectrum disorder (ASD).Conversely, several candidate genes for ASD, schizophrenia, and ID affect primary cilia function.Despite these findings and their critical function as signaling hubs, roles of primary cilia in the ASD pathomechanism remain largely unexplored.Here, we analysed the function of CEP41 in human corticogenesis.It encodes a centrosomal protein located at the basal body and the ciliary axoneme and is mutated in ASD patients and in Joubert syndrome, a ciliopathy with high incidence of ASD.To gain insights into its role in ASD aetiology, we characterised human cortical organoids carrying the CEP41 R242H point mutations found in ASD patients.This mutation did not interfere with CEP41's ciliary localisation but cilia were shorter and had lower levels of tubulin polyglutamylation indicative of altered cilia stability and signalling.Moreover, scRNAseq analyses revealed that in interneurons and their progenitors the altered expression of several transcription factors with critical roles in interneuron development coincided with changes in interneuron differentiation.The CEP41 mutation also caused decreased cortical progenitor proliferation and an augmented formation of upper layer cortical neurons.In addition, we are investigating the effects of the R242H mutation on the morphology of projection neurons and on neuronal network activity.Taken together, these findings indicate that CEP41 controls excitatory and inhibitory neuron differentiation, alterations in which might lead to an excitation/inhibition imbalance that is widely recognized as a convergent mechanism underlying neurodevelopmental disorders.No ethical approval is required.