Functional characterization of FSD1L: a novel “master regulator” of neurodevelopment?

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2021 

This project focuses on a novel gene, FSD1L, encoding a protein of unknown function highly expressed in the fetal and adult brain. We recently identified FSD1L recessive mutations in patients from 3 families presenting developmental delay, intellectual disability, epilepsy and spasticity, and a brain malformation characterized by corpus callosum defects, reduced white matter and mild hydrocephalus.Our preliminary work suggests many relevant functions for FSD1L in neurodevelopment. Patient-derived neural stem cells showed impaired ability to migrate and to differentiate into neurons, as well as a severe dysregulation of hundreds of genes, including transcription factors and signaling molecules involved in neurodevelopment. We also showed that dysfunctional FSD1L may impair the centrosome, a subcellular organelle essential to ensure cell divisions and a proper transduction of signaling pathways through the primary cilium.The project proposes to further characterize the multifaceted functions of this novel gene by using cell lines in which FSD1L is silenced or overexpressed, as well as patient-derived cells differentiated towards neural lineages. In aim 1, we will employ well-consolidated techniques to finely dissect the FSD1L neurodevelopmental phenotype in neuronal and glial cells; in aim 2, we will characterize the role of FSD1L at the centrosome during different stages of the cell cycle, and its ability to interact with centrosomal and ciliary proteins through specific domains; finally, in aim 3, we will evaluate the transcriptional defects of FSD1L-mutant neuronal cells, and will explore the hypothesis that, in such cells, nuclear FSD1L can act as a global regulator of transcription. We believe this project will increase knowledge of the complex mechanisms underlying regulation of brain development, with translational impact on other neurodevelopmental disorders.