CBP and SRF co-regulate dendritic growth and synaptic maturation

The CREB-binding protein (CBP) exerts tight control of developmental processes. Here, we investigated the consequences of its selective ablation in newborn neurons. Mice in which CBP was eliminated during neuronal differentiation showed perinatal death and defective diaphragm innervation. Adult-born neurons also showed impaired growth and maturation after inducible and restricted CBP loss in dentate gyrus neuroprogenitors. Consistent with these in vivo findings, cultured neurons displayed impaired outgrowth, immature spines, and deficient activity-dependent synaptic remodeling after CBP ablation. These deficits coincided with broad transcriptional changes affecting genes involved in neuronal growth and plasticity. The affected gene set included many predicted targets of both CBP and the serum response factor (SRF), an activity-regulated transcription factor involved in structural plasticity. Notably, increasing SRF activity in a CBP-independent manner ameliorated the transcriptional, synaptic, and growth defects. These results underscore the relevance of CBP–SRF interactions during neuronal outgrowth and synaptic maturation, and demonstrate that CBP plays an essential role in supporting the gene program underlying the last steps of neuronal differentiation, both during development and in the adult brain.BdB is the recipient of a “Juan de La Cierva” contract from the Spanish Ministry of Economy and Competitiveness (MINECO). MTL-C is supported by a contract (BES-2017-081298) from Spanish Ministry of Economy and Competitiveness (MINECO). This research was supported by grants SAF2017-87928-R, BFU2016-77605-P, PCIN-2015-192-C02-01 and PCIN-2015-192-C02-02 (both grants are part of the ERA-NET NEURON JTC2015 project ChromISyn), and SEV-2017-0723 from MINECO co-financed by ERDF, grant PROMETEO/2016/026 from the Generalitat Valenciana, grant RGP0039/2017 from the Human Frontiers Science Program Organization (HFSPO), and a grant from the Alicia Koplowitz Foundation. The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa”.Peer reviewe