Transgenic modeling of Ndr2 gene amplification reveals disturbance of hippocampus circuitry and function
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Transgenic modeling of Ndr2 gene amplification reveals disturbance of hippocampus circuitry and function. / Madencioglu, Deniz A; Çalışkan, Gürsel; Yuanxiang, Pingan; Rehberg, Kati; Demiray, Yunus E; Kul, Emre; Engler, Alexander; Hayani, Hussam; Bergado-Acosta, Jorge R; Kummer, Anne; Müller, Iris; Song, Inseon; Dityatev, Alexander; Kähne, Thilo; Kreutz, Michael R; Stork, Oliver.
In: ISCIENCE, Vol. 24, No. 8, 20.08.2021, p. 102868.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Transgenic modeling of Ndr2 gene amplification reveals disturbance of hippocampus circuitry and function
AU - Madencioglu, Deniz A
AU - Çalışkan, Gürsel
AU - Yuanxiang, Pingan
AU - Rehberg, Kati
AU - Demiray, Yunus E
AU - Kul, Emre
AU - Engler, Alexander
AU - Hayani, Hussam
AU - Bergado-Acosta, Jorge R
AU - Kummer, Anne
AU - Müller, Iris
AU - Song, Inseon
AU - Dityatev, Alexander
AU - Kähne, Thilo
AU - Kreutz, Michael R
AU - Stork, Oliver
N1 - © 2021 The Author(s).
PY - 2021/8/20
Y1 - 2021/8/20
N2 - Duplications and deletions of short chromosomal fragments are increasingly recognized as the cause for rare neurodevelopmental conditions and disorders. The NDR2 gene encodes a protein kinase important for neuronal development and is part of a microduplication region on chromosome 12 that is associated with intellectual disabilities, autism, and epilepsy. We developed a conditional transgenic mouse with increased Ndr2 expression in postmigratory forebrain neurons to study the consequences of an increased gene dosage of this Hippo pathway kinase on brain circuitry and cognitive functions. Our analysis reveals reduced terminal fields and synaptic transmission of hippocampal mossy fibers, altered hippocampal network activity, and deficits in mossy fiber-dependent behaviors. Reduced doublecortin expression and protein interactome analysis indicate that transgenic Ndr2 disturbs the maturation of granule cells in the dentate gyrus. Together, our data suggest that increased expression of Ndr2 may critically contribute to the development of intellectual disabilities upon gene amplification.
AB - Duplications and deletions of short chromosomal fragments are increasingly recognized as the cause for rare neurodevelopmental conditions and disorders. The NDR2 gene encodes a protein kinase important for neuronal development and is part of a microduplication region on chromosome 12 that is associated with intellectual disabilities, autism, and epilepsy. We developed a conditional transgenic mouse with increased Ndr2 expression in postmigratory forebrain neurons to study the consequences of an increased gene dosage of this Hippo pathway kinase on brain circuitry and cognitive functions. Our analysis reveals reduced terminal fields and synaptic transmission of hippocampal mossy fibers, altered hippocampal network activity, and deficits in mossy fiber-dependent behaviors. Reduced doublecortin expression and protein interactome analysis indicate that transgenic Ndr2 disturbs the maturation of granule cells in the dentate gyrus. Together, our data suggest that increased expression of Ndr2 may critically contribute to the development of intellectual disabilities upon gene amplification.
U2 - 10.1016/j.isci.2021.102868
DO - 10.1016/j.isci.2021.102868
M3 - SCORING: Journal article
C2 - 34381982
VL - 24
SP - 102868
JO - ISCIENCE
JF - ISCIENCE
SN - 2589-0042
IS - 8
ER -