CREB (cyclic AMP response element binding protein) binding protein (CBP, CREBBP) is a ubiquitously expressed transcription coactivator with intrinsic histone acetyltransferase (KAT) activity. Germline mutations within the CBP gene are known to cause Rubinstein-Taybi syndrome (RSTS), a developmental disorder characterized by intellectual disability, specific facial features and physical anomalies. Here, we investigate mechanisms of CBP function during brain development in order to elucidate morphological and functional mechanisms underlying the development of RSTS. Due to the embryonic lethality of conventional CBP knockout mice, we employed a tissue specific knockout mouse model (hGFAP-cre::CBPFl/Fl, mutant mouse) to achieve a homozygous deletion of CBP in neural precursor cells of the central nervous system.Our findings suggest that CBP plays a central role in brain size regulation, correct neural cell differentiation and neural precursor cell migration. We provide evidence that CBP is both important for stem cell viability within the ventricular germinal zone during embryonic development and for unhindered establishment of adult neurogenesis. Prominent histological findings in adult animals include a significantly smaller hippocampus with fewer neural stem cells. In the subventricular zone, we observe large cell aggregations at the beginning of the rostral migratory stream due to a migration deficit caused by impaired attraction from the CBP-deficient olfactory bulb. The cerebral cortex of mutant mice is characterized by a shorter dendrite length, a diminished spine number, and a relatively decreased number of mature spines as well as a reduced number of synapses.In conclusion, we provide evidence that CBP is important for neurogenesis, shaping neuronal morphology, neural connectivity and that it is involved in neuronal cell migration. These findings may help to understand the molecular basis of intellectual disability in RSTS patients and may be employed to establish treatment options to improve patients' quality of life.

中文翻译：

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转录共激活剂和组蛋白乙酰转移酶CBP调节神经前体细胞的发育和迁移。

CREB（环状AMP应答元件结合蛋白）结合蛋白（CBP，CREBBP）是一种普遍表达的具有固有组蛋白乙酰转移酶（KAT）活性的转录共激活因子。已知CBP基因内的种系突变会引起Rubinstein-Taybi综合征（RSTS），这是一种发育障碍，其特征是智力残疾，特定的面部特征和身体异常。在这里，我们研究脑发育过程中CBP功能的机制，以阐明潜在的RSTS发育的形态学和功能机制。由于常规CBP基因敲除小鼠的胚胎致死性，我们采用了组织特异性基因敲除小鼠模型（hGFAP-cre :: CBPF1 / F1，突变小鼠）在中枢神经系统的神经前体细胞中实现了CBP的纯合缺失。我们的发现表明，CBP在调节大脑大小，纠正神经细胞分化和神经前体细胞迁移中起着核心作用。我们提供的证据表明CBP既对胚胎发育过程中心室发芽区内的干细胞活力重要，又对成人神经发生的无阻碍建立均重要。在成年动物中突出的组织学发现包括海马体明显较小，神经干细胞较少。在脑室下区域，由于CBP缺陷型嗅球的吸引力减弱引起的迁移缺陷，我们在鼻尖迁移流的开始处观察到大量细胞聚集。突变小鼠的大脑皮层的特征是树突较短，脊柱数目减少，总之，我们提供的证据表明，CBP对于神经发生，塑造神经元形态，神经连通性很重要，并且参与神经元细胞迁移。这些发现可能有助于了解RSTS患者智力障碍的分子基础，并可用于建立治疗方案以改善患者的生活质量。