Auto‐regulatory interactions between NFI occupancy and ETV1 direct the timing of gene expression in late maturing neurons (539.10)

Developmental timing mechanisms play an essential role in nervous system development, and their disruption during synapse maturation is implicated in neurodevelopmental disorders. To examine how the timing of gene expression related to synapse formation is regulated during neuronal maturation, we used cerebellar tissues from gene knockout mouse and lentiviral transduction of mouse cerebellar granule neuron (CGN) cultures together with microarray, qRT‐PCR, and chromatin immunoprecipitation assays. We found that Nuclear Factor One (NFI) regulates the temporal expression of genes required for dendrite and synapse formation via its delayed binding to their promoters in developing CGNs. Further, a second transcription factor, ETV1, directly binds to and is required for the NFI occupancy and expression of numerous NFI‐dependent genes in vitro and in vivo. ETV1 binds to and activates the Etv1 gene itself, and this auto‐regulatory loop is induced prior to the activation of downstream target genes. We propose that ETV1 activates NFI temporal occupancy of late‐expressed genes in a stepwise manner by initial positive feedback up‐regulation of the Etv1 gene followed by activation of downstream late genes as ETV1 expression increases. Sequential transcription factor auto‐regulation and subsequent binding to downstream promoters provides a developmental timing mechanism for dendrite/synapse gene expression. Grant Funding Source : Supported by PHS grant NS063047 to DLK