CBP and P300 are individually indispensable for the differentiation of neural progenitors and are jointly required for their proliferation

Abstract

During development, changes in the genomic profiles of histone acetylation accompany the onset and maintenance of the gene expression programs associated with neuronal differentiation and the formation of neuronal circuits. The paralog lysine acetyltransferases (KAT) CREB binding protein (CBP) and E1A binding protein (p300) are both essential for the normal development of the nervous system. In fact, KAT3 deficiency causes Rubinstein-Taybi syndrome (RSTS), a neurodevelopmental disorder characterized by abnormal brain development, ocular anomalies, intellectual disability and other symptoms. The precise function of these chromatin-modifying enzymes during the development of the central nervous system has not been clearly stated. Here, throughout a combination of in vitro and in vivo approaches and the use of different credrivers, we dissect the functions of CBP and p300 in different steps of neural development. We first demonstrate that the proliferation of neural progenitors in vitro is not affected in the loss of CBP or p300 but is seriously comprised when both proteins are absent. In addition, we observe that the elimination of either CBP or p300 disrupts early neuronal differentiation in vitro, although only CBP seems to be required for terminal retinal cells differentiation in vivo. Similarly to our observations in neuroprogenitors, the maintenance of RGC identity does not individually require either one of the KAT3 proteins, but at least one of the two proteins must be expressed for their preservation. Together these results identify unique and shared roles for these two important epigenetic factors throughout development and demonstrate that CBP plays a more prominent role than p300 during neuronal differentiation in the retina.