BDNF activates an NFI-dependent neurodevelopmental timing program by sequestering NFATc4

How intrinsic and extrinsic signals are coordinated to regulate synaptic maturation and its timing is an important question for neurodevelopment and its disorders. We investigated the influence of the neurotrophin BDNF on the developmental timing of a dendrite/synapse-related gene program controlled by nuclear factor I (NFI) in maturing cerebellar granule neurons (CGNs). BDNF accelerated the onset of NFI-regulated late-gene expression and NFI temporal occupancy in CGN cultures in a MEK5/ERK5-dependent manner. BDNF and NFI occupancy were mutually regulating, with BDNF enhancing the temporal binding of NFI to the Bdnf4 promoter itself. Moreover, BDNF induced phosphorylation and accelerated the departure of the trans-repressor NFATc4 from NFI late-gene promoters, including Bdnf4, which is permissive for NFI binding. BDNF dismissal of NFATc4 from late genes was linked to MEK5/ERK5-dependent sequestration of NFATc4 in the cis-Golgi, an event mirrored in CGNs developing in vivo. These studies reveal an expanded autoregulatory gene network for NFI temporal occupancy involving BDNF and NFATc4 extranuclear sequestration. Based on these and earlier findings, NFATc4 integrates intrinsic developmental signaling from membrane potential/calcineurin and autocrine/paracrine BDNF/TrkB to control initiation of NFI occupancy in maturing CGNs. We also identify a local Bdnf/Etv1 gene circuit within the larger NFI autoregulatory network.