Uncovering a novel function for NRXN1a using cellular models of early hindbrain neurodevelopment

Objective

Neurexin1a (NRXN1a) is involved in the pathology of multiple neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), schizophrenia, and intellectual disability. Until now, the mechanism has been mainly attributed to its function at neuronal synapses. Here, I aim to break new ground by uncovering the function of NRXN1a in the early stage of neural differentiation of induced pluripotent stem cells (iPSCs), where a short peak of its expression has been identified. Intriguingly, despite the strong associations of NRXN1a with NDDs, such a study is missing. To elucidate the role of NRXN1a at the early stage of neural differentiation, I will use two different complementary iPSC-derived cellular models of hindbrain neural development from healthy controls, an ASD-diagnosed patient with a biallelic mutation in NRXN1a, and a CRISPR-edited NRXN1a-deficient iPSC line, enabling simultaneous investigation of distinct aspects of the NRXN1a-deficient phenotype. Using this approach, I first aim to decipher the molecular mechanisms of NRXN1a function and its involvement in the regulation of intracellular calcium levels. Next, I aim to model the outcomes of NRXN1a deficiency in a disease-relevant setup using cerebellar organoids. Together, this project will advance our understanding of the function of NRXN1a in the early hindbrain differentiation. It will help elucidate the structural and functional abnormalities observed in ASD-affected cerebella and enable a more precise interpretation of phenotypes observed in NRXN1a-deficient patients. Since increasing evidence suggests that the clinical manifestations of various NDDs may be underlined by a common molecular mechanism, the results have the potential to be beneficial also for other studies on NDDs.