Foxp1 regulates neurogenesis by modulating the Notch pathway

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Mutations in Foxp1 have been linked to neurodevelopmental disorders including intellectual disability and autism, however, the underlying molecular mechanisms remain ill-defined. Here work from Luca Braciolli demonstrates utilizing RNA- and chromatin immunoprecipitation (ChIP)-sequencing that Foxp1 directly regulates genes controlling neurogenesis. We show that Foxp1 is expressed in embryonic neural stem cells (NSCs) and modulation of Foxp1 expression impacts both neuron and astrocyte differentiation. Using a murine model of cortical development, Foxp1-knockdown in utero was found to reduce NSC differentiation and migration during corticogenesis. Furthermore, transplantation of Foxp1-knockdown NSCs in neonatal mice after hypoxia-ischemia (HI) challenge demonstrated that Foxp1 is also required for neuronal differentiation and functionality in vivo. Foxp1 was found to repress the expression of Notch pathway genes including the Notch-ligand Jagged1, resulting in inhibition of Notch signaling.  Finally, blockade of Jagged1 in Foxp1-knockdown NSCs rescued neuronal differentiation in vitro. Together these data support a novel role for Foxp1 in regulating embryonic NSC differentiation by modulating Notch signaling.

This work is part of a collaboration with the Nijboer and Pasterkamp Labs and has recently been accepted for publication in Stem Cell Reports.