Neuronal activity control by products of Foxg1-responsive, Tdark Rnf genes

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2022

FOXG1 gene governs anterior brain development and tunes maturation and activity of cerebral cortex. A number of FOXG1 mutations lead to the FOXG1 syndrome, a complex and rare disease including epilepsy, autism and severely impaired cognition. Among genes responding to experimental Foxg1 manipulation, there are 14 poorly characterized Rnf genes, putatively encoding for specific E3 enzymes promoting the turnover of other proteins. Products of such Rnf genes interact with effectors implicated in electrical activity of nerve cells and, in turn, electrical activity influences the activity of these Rnf genes. Based on that, we predict that these Rnf genes likely contribute to mediate the interplay occurring between Foxg1 and neuronal activity. The validation of this prediction will strenghten the emerging model of a unique factor (the Foxg1 protein) controlling the activity of its target genes at multiple levels, a concept of remarkable interest for central nervous system evolution. Not less, it will suggest novel, druggable molecular targets, suitable for pharmacological mitigation of FOXG1 syndrome.
To test this prediction, firstly, we will identify presumptive targets of these E3 enzymes, by comparing the abundance of a large number of individual proteins in cerebral cells producing increased or decreased amounts of such enzymes. Next, limited to selected cases, we will confirm that differences in abundance observed originated from a change in degradation rate of the corresponding proteins. Finally, we will quantify the impact that experimental manipulation of select Rnf genes encoding for these E3 enzymes has on electrical activity of nerve cells.