The transcriptional coactivator and histone acetyltransferase CBP regulates neural precursor cell development and migration
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The transcriptional coactivator and histone acetyltransferase CBP regulates neural precursor cell development and migration. / Schoof, Melanie; Launspach, Michael; Holdhof, Dörthe; Nguyen, Lynhda; Engel, Verena; Filser, Severin; Peters, Finn; Immenschuh, Jana; Hellwig, Malte; Niesen, Judith; Mall, Volker; Ertl-Wagner, Birgit; Hagel, Christian; Spohn, Michael; Lutz, Beat; Sedlacik, Jan; Indenbirken, Daniela; Merk, Daniel J; Schüller, Ulrich.
in: ACTA NEUROPATHOL COM, Jahrgang 7, Nr. 1, 05.12.2019, S. 199.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - The transcriptional coactivator and histone acetyltransferase CBP regulates neural precursor cell development and migration
AU - Schoof, Melanie
AU - Launspach, Michael
AU - Holdhof, Dörthe
AU - Nguyen, Lynhda
AU - Engel, Verena
AU - Filser, Severin
AU - Peters, Finn
AU - Immenschuh, Jana
AU - Hellwig, Malte
AU - Niesen, Judith
AU - Mall, Volker
AU - Ertl-Wagner, Birgit
AU - Hagel, Christian
AU - Spohn, Michael
AU - Lutz, Beat
AU - Sedlacik, Jan
AU - Indenbirken, Daniela
AU - Merk, Daniel J
AU - Schüller, Ulrich
PY - 2019/12/5
Y1 - 2019/12/5
N2 - 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.
AB - 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.
U2 - 10.1186/s40478-019-0849-5
DO - 10.1186/s40478-019-0849-5
M3 - SCORING: Journal article
C2 - 31806049
VL - 7
SP - 199
JO - ACTA NEUROPATHOL COM
JF - ACTA NEUROPATHOL COM
SN - 2051-5960
IS - 1
ER -