The transcriptional coactivator and histone acetyltransferase CBP regulates neural precursor cell development and migration

• Main Authors: Melanie Schoof, Michael Launspach, Dörthe Holdhof, Lynhda Nguyen, Verena Engel, Severin Filser, Finn Peters, Jana Immenschuh, Malte Hellwig, Judith Niesen, Volker Mall, Birgit Ertl-Wagner, Christian Hagel, Michael Spohn, Beat Lutz, Jan Sedlacik, Daniela Indenbirken, Daniel J. Merk, Ulrich Schüller
• Format: Article
• Language: English
• Published: BMC 2019-12-01
• Series: Acta Neuropathologica Communications
• Subjects: Creb binding protein (CREBBP; CBP); Rubinstein-Taybi syndrome (RSTS); Neural precursor cell migration; Adult neurogenesis; Neural differentiation
• Online Access: https://doi.org/10.1186/s40478-019-0849-5

Abstract 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::CBP Fl/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.