PhD Student Institut Imagine, INSERM, Université Paris Cité, Ile-de-France, France
Abstract: The functioning of the human nervous system relies on the emergence, during development, of a highly organized cellular diversity. Even slight disruptions in its cellular composition can have major consequences, contributing to neurodevelopmental disorders (NDD). Through whole-genome genomics approaches, we recently discovered recessive mutations in PRDM13 in patients affected by a rare and severe NDD, marked by cerebellar and brainstem hypoplasia. PRDM13 encodes a neural-specific member of the PRDM protein family of epigenetic regulators, known to modulate cell fate choices decision in various developmental contexts. In mouse models, Prdm13 was previously shown to impact cell fate choices in the spinal cord. Our functional analyses in the zebrafish model indicate that loss-of-function of prdm13 also impairs the generation of cerebellar inhibitory neurons, notably Purkinje cells, and induces profound perturbations in neuronal cell fate specification in the brainstem. However, the molecular mechanisms underlying these defects remain to be deciphered, in particular in the human context. Leveraging a cytidine base editing approach, we obtained isogenic clones of human induced pluripotent stem cells carrying a nonsense mutation in PRDM13 and derived cerebellar and spinal organoids, using in-house optimized protocols. We are currently characterizing these mutant organoids, using immunohistochemistry, bulk and single-cell transcriptomics. Our preliminary analyses support a multifaceted role for PRDM13 in orchestrating cell fate specification during human posterior brain development. These models will also provide a valuable opportunity to elucidate, within a human context, the epigenetic mechanisms involving PRDM13 that regulate posterior nervous system development.
Funding Source: Works supported by funds from INSERM, CNRS, Université Paris Cité, Institut Imagine and Institut Jacques Monod. This project benefits from ANR and the patient association CSC grants.
