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CBP and SRF co-regulate dendritic growth and synaptic maturation.

Beatriz del Blanco, Deisy Guiretti, Romana Tomasoni, Maria T. Lopez-Cascales, Rafael Muñoz-Viana, Michal Lipinski, Marilyn Scandaglia, Yaiza Coca, Román Olivares, Luis M. Valor, Eloisa Herrera and Angel Barco.

Cell Death & Diff.
Published: March 8th, 2019

The development and refinement of brain circuits depends on the action of a network of transcription factors and epigenetic regulators. These proteins control neuronal differentiation and maturation. Among them, the CREB-binding protein (CBP) is a lysine acetyltransferase (KAT) and transcriptional scaffold protein that is known to exert tight control of developmental processes. Although seminal experiments in knockout mice have demonstrated that CBP is essential during early development of the central nervous system, little is still known about the gene expression programs later regulated by CBP in neurons.

In this study, we investigate the consequences of the selective ablation of CBP 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, CBP-depleted cultured neurons displayed impaired outgrowth, immature spines, and deficient activity-dependent synaptic remodeling. These deficits coincided with broad transcriptional changes affecting genes involved in neuronal growth and plasticity, including many 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. Our research also contributes to clarify the etiology of neurological symptoms in Rubinstein-Taybi syndrome, a rare intellectual disability disorder caused by mutation in the gene encoding CBP, which opens new avenues for therapeutic intervention.

This work was carried out in the laboratory of Prof. Angel Barco at the Instituto de Neurociencias (CSIC-UMH), and includes the collaboration of researchers from the laboratory of Dr. Herrera and a visitor researcher from IRCCS Humanitas (Milán, Italia).

From left to right: Michal Lipinski, Maria Teresa Cascales, Beatriz del Blanco, Luis Miguel Valor, Yaiza Coca, Eloisa Herrera, Rafael Muñoz-Viana, Angel Barco, Román Olivares, Marilyn Scandaglia y Deisy Guiretti.

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