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

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::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.

CREBBP knockdown suppressed proliferation and promoted chemo-sensitivity via PERK-mediated unfolded protein response in ovarian cancer

“…CBP also acts as a lysine acetyltransferase to regulate protein expressions and functions via direct acetylation e.g., DOT1L, BCAT2, KDM2B and STX17 [14][15][16]25]. Due to the transcription-promoting and LAT activity, CBP is involved in multiple cellular functions and pathological processes especially in tumorigenesis [26][27][28][29][30], but its effect on ovarian cancer has not been fully explored.…”

Olfactory Malformations in Mendelian Disorders of the Epigenetic Machinery

“…Similarly, cAMP-response element-binding protein ( CREBBP , #600140 ) gene and of E1A Binding Protein P300 ( EP300, #602700) gene, both involved in RSTS, can control the expression of numerous genes important for cell differentiation and maturation ( Goodman and Smolik, 2000 ; Zimmermann et al, 2007 ). Reduced levels of functioning protein lead to disrupted gene expression/suppression and dysregulated differentiation and maturation of different classes of neurons during development ( Wang et al, 2010 ; del Blanco et al, 2019 ; Schoof et al, 2019 ). Direct evidence of aberrant neuronal migration has also been reported in WVS.…”

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

“…Several other mouse models presented with deficits of callosal projections. For example in Cbp knockout mice (Rubinstein–Taybi Syndrome) a reduced size of the corpus callosum was found [ 319 ], similar to the phenotype of mutants for the chromatin remodelling complex members Prdm8 and HP1γ [ 320 , 321 ]. Furthermore, knockdown of the chromatin remodeler Chd8 in the neocortex impaired dendrite and axonal growth and branching of upper-layer callosal projection neurons, and resulted in delayed migration of cortical neurons at E18.5, as the majority of labelled cells remained in the VZ/SVZ [ 322 ].…”

“…MRXFH1: Mental retardation, microcephaly, short stature, unusual facial appearance, hypotonia 300032, 301040, 309580 Hemizygote males: Embryonic lethal. Heterozygote female cKO: Impaired spatial, contextual fear and novel object recognition memory, stunted growth Sex-specific repression of miR-137, synaptic defects, loss of retinal interneurons (amacrine and horizontal cells) [ 95 , 299 – 308 , 473 – 476 ] AUTS2 PRC complex H2AUb1 K119 Autosomal dominant form of syndromic mental retardation ID, ASD, microcephaly, short stature and cerebral palsy 615834 Defects in: motor skills, vocalisation following maternal separation, neurocognitive ability, exploration, recognition and associative memory and learning and memory formation Impaired progenitor migration, increased in cell death during in vitro corticogenesis, premature neuronal differentiation, altered neuronal morphology [ 123 , 124 , 477 ] CBP Acetylation of H3K9, H3K14 and H3K27 Rubinstein-Taybi syndrome ID, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features 180849 Microcephaly, anxiety, reduced exploration and curiousity, brain structure abnormalities in the corpus callosum, hippocampus and olfactory bulb Increased progenitor proliferation, reduced glutamatergic and gabaergic neuron generation, astrocytes and oligodendrocytes generation [ 41 , 68 , 162 – 165 , 319 , 355 – 359 , 446 ] CDK5RAP2 – Centrosomal protein Autosomal recessive primary microcephaly-3 (MCPH3) ID, Microcephaly 604804, 608201 Microcephaly with hypo...…”