Abstract
Forkhead Box P (FOXP) transcriptional repressors play a major role in brain development and their dysfunction leads to human cognitive disorders. However, little is known about how the activity of these proteins is regulated. Here, we show that FOXP1 SUMOylation at lysine 670 is required for recruiting the co-repressor CtBP1 and transcriptional repression. FOXP1 SUMOylation is tightly controlled by neuronal activity, in which synapse to nucleus signalling, mediated via NMDAR and L-type calcium channels, results in rapid FOXP1 deSUMOylation. Knockdown of FOXP1 in cultured cortical neurons stunts dendritic outgrowth and this phenotype cannot be rescued by replacement with a non-SUMOylatable FOXP1-K670R mutant, indicating that SUMOylation of FOXP1 is essential for regulation of proper neuronal morphogenesis. These results suggest that activity-dependent SUMOylation of FOXP1 may be an important mediator of early cortical development and neuronal network formation in the brain.
Highlights
Forkhead Box P (FOXP) proteins are a subfamily of transcription factors that bind to promoter and enhancer sequences in many genes via a forkhead DNA binding motif to spatially and temporally control the expression of a wide range of genes[1]
We demonstrate that endogenous FOXP1 is SUMOylated at K670 in rat neurons and this is required for efficient transcriptional repression, likely by promoting binding to the transcriptional co-repressor C-terminal-binding protein 1 (CtBP1)
FOXP1 SUMOylation is essential for the proper neuronal morphogenesis that is required for cortical development and neuronal network formation
Summary
Forkhead Box P (FOXP) proteins are a subfamily of transcription factors that bind to promoter and enhancer sequences in many genes via a forkhead DNA binding motif to spatially and temporally control the expression of a wide range of genes[1]. FOXP family members are involved in embryonic morphogenesis[1] and they play key roles in regulating the development and differentiation of cells in many tissue types. Inhibition of Foxp[1] expression in the mouse cortex impairs neuronal migration, polarisation and the maturation of dendritic processes[10, 11]. Inappropriate regulation of the SUMO pathway is a common factor in many neurological and neurodegenerative diseases[13] Both FOXP1 and FOXP2 bind SUMO E3 ligases, and have been demonstrated to be SUMO substrates[14]. SUMOylation of cerebellar FOXP2 in mouse neonates modifies its transcriptional activity to regulate Purkinje cell development, dendritic outgrowth and arborization, and is required for correct cerebellar motor function and vocal communication[15, 16]. FOXP1 SUMOylation is essential for the proper neuronal morphogenesis that is required for cortical development and neuronal network formation
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