Cux-2 Controls the Proliferation of Neuronal Intermediate Precursors of the Cortical Subventricular Zone

Cubelos, Beatriz; Sebastián-Serrano, Álvaro; Kim, Seonhee; Moreno-Ortiz, Carmen; Redondo, Juan Miguel; Walsh, Christopher A.; Nieto, Marta

doi:10.1093/cercor/bhm199

Cited by 102 publications

(107 citation statements)

References 38 publications

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“…5A–D). We also observed a significantly reduced number of Ctip2 (early‐born)‐ and Cux1 (late‐born)‐positive neurons (Arlotta et al, 2005; Cubelos et al, 2008) in the developing cortex at E18.5 (Ctip2: PlexinA1 +/ + 41.93 ± 15.7, PlexinA1 −/− 28.41 ± 6.7 [ P < 0.3]; Cux1: PlexinA1 +/ + 82.07 ± 6.4, PlexinA1 −/− 58.24 ± 4.3 [ P < 0.005]; Fig. 5E–I).…”

Section: Resultsmentioning

confidence: 55%

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Altered proliferative ability of neuronal progenitors in PlexinA1 mutant mice

Andrews

Davidson

Tamamaki

et al. 2015

J of Comparative Neurology

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Cortical interneurons are generated predominantly in the medial ganglionic eminence (MGE) and migrate through the ventral and dorsal telencephalon before taking their final positions within the developing cortical plate. Previously we demonstrated that interneurons from Robo1 knockout (Robo1−/−) mice contain reduced levels of neuropilin 1 (Nrp1) and PlexinA1 receptors, rendering them less responsive to the chemorepulsive actions of semaphorin ligands expressed in the striatum and affecting their course of migration (Hernandez‐Miranda et al. [2011] J. Neurosci. 31:6174–6187). Earlier studies have highlighted the importance of Nrp1 and Nrp2 in interneuron migration, and here we assess the role of PlexinA1 in this process. We observed significantly fewer cells expressing the interneuron markers Gad67 and Lhx6 in the cortex of PlexinA1 −/− mice compared with wild‐type littermates at E14.5 and E18.5. Although the level of apoptosis was similar in the mutant and control forebrain, proliferation was significantly reduced in the former. Furthermore, progenitor cells in the MGE of PlexinA1 −/− mice appeared to be poorly anchored to the ventricular surface and showed reduced adhesive properties, which may account for the observed reduction in proliferation. Together our data uncover a novel role for PlexinA1 in forebrain development. J. Comp. Neurol. 524:518–534, 2016. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 55%

“…ab18465, RRID: AB_2064130) to Ctip2 recognizes an epitope between amino acids 1 and 150 of human CTIP2. Ctip2 immunohistochemistry carried out on wild‐type embryonic mouse forebrain sections specifically labels lower layer pyramidal neurons (Cubelos et al, 2008; Yeh et al, 2014). …”

Section: Methodsmentioning

confidence: 99%

Altered proliferative ability of neuronal progenitors in PlexinA1 mutant mice

Andrews

Davidson

Tamamaki

et al. 2015

J of Comparative Neurology

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“…Cux2 particularly regulates the proliferation of intermediate neuronal precursors in the subventricular zone of the developing brain [22]. Cux2 deletion in mice resulted in altered dendritogenesis, synaptogenesis and spine formation in pyramidal glutamatergic/ GABAergic neurons [12].…”

Section: Discussionmentioning

confidence: 99%

Possible association of CUX1 gene polymorphisms with antidepressant response in major depressive disorder

Sasayama

Hiraishi

Tatsumi³

et al. 2012

Pharmacogenomics J

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Association between response to antidepressant treatment and genetic polymorphisms was examined in two independent Japanese samples of patients with major depressive disorder (MDD). Genome-wide approach using the Illumina Human CNV370-quad Bead Chip was utilized in the analysis of the 92 MDD patients in the first sample.Eleven non-intergenic SNPs with uncorrected allelic P value < 0.0001 were selected for the subsequent association analyses in the second sample of 136 MDD patients.Difference in allele distribution between responders and nonresponders were found in the second stage sample for rs365836 and rs201522 of the CUX1 gene (P = 0.005 and 0.004, respectively). The allelic P values for rs365836 and rs201522 in both samples combined were 0.0000023 and 0.0000040, respectively. Our results provide the first evidence that polymorphisms of the CUX1 gene may be associated with response to antidepressant treatment in Japanese patients with MDD.

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“…As a consequence, Af9 −/− brains are smaller than controls and contain fewer BrdU-positive cells in upper layer positions of the cerebral cortex. However, Cux2 −/− brains are bigger, display more BrdUpositive neurons in upper layers, and have tightly packed upper layers (8). Thus, both AF9 and CUX2 differentially influence IPCs, where CUX2 promotes cell cycle exit at the time of upper layer formation and AF9 prevents premature exit from the cell cycle and further inhibits the acquisition of lower layer identity by suppressing TBR1 expression at the time of upper layer formation.…”

Section: Discussionmentioning

confidence: 99%

“…Little is known about AF9 function in the CNS, although its expression pattern implies a role during development of the forebrain and cerebellum (6). In the mouse forebrain, Af9 is transcribed in the subventricular zone (SVZ), a neurogenic compartment that harbors progenitors for upper layer neurons (7,8). Af9 is also expressed in neurons dispersed over all cortical layers and diverges in this respect from other SVZ markers, such as Svet1 and Cux2 (6).…”

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confidence: 99%

Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex

Büttner

Johnsen

Kügler

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Mutations of leukemia-associated AF9/MLLT3 are implicated in neurodevelopmental diseases, such as epilepsy and ataxia, but little is known about how AF9 influences brain development and function. Analyses of mouse mutants revealed that during cortical development, AF9 is involved in the maintenance of TBR2-positive progenitors (intermediate precursor cells, IPCs) in the subventricular zone and prevents premature cell cycle exit of IPCs. Furthermore, in postmitotic neurons of the developing cortical plate, AF9 is implicated in the formation of the six-layered cerebral cortex by suppressing a TBR1-positive cell fate mainly in upper layer neurons. We show that the molecular mechanism of TBR1 suppression is based on the interaction of AF9 with DOT1L, a protein that mediates transcriptional control through methylation of histone H3 lysine 79 (H3K79). AF9 associates with the transcriptional start site of Tbr1, mediates H3K79 dimethylation of the Tbr1 gene, and interferes with the presence of RNA polymerase II at the Tbr1 transcriptional start site. AF9 expression favors cytoplasmic localization of TBR1 and its association with mitochondria. Increased expression of TBR1 in Af9 mutants is associated with increased levels of TBR1-regulated expression of NMDAR subunit Nr1. Thus, this study identified AF9 as a developmental active epigenetic modifier during the generation of cortical projection neurons.A F9/MLLT3 is one of multiple fusion partners of the histone methyltransferase MLL1 in acute leukemia (1, 2). However, mutations of the AF9/MLLT3 gene alone are not associated with leukemia but are implicated in anterior homeotic transformations during mouse development (3), and in neurodevelopmental diseases, such as mental retardation, epilepsy, and ataxia in human patients (4,5). Little is known about AF9 function in the CNS, although its expression pattern implies a role during development of the forebrain and cerebellum (6). In the mouse forebrain, Af9 is transcribed in the subventricular zone (SVZ), a neurogenic compartment that harbors progenitors for upper layer neurons (7,8). Af9 is also expressed in neurons dispersed over all cortical layers and diverges in this respect from other SVZ markers, such as Svet1 and Cux2 (6). On the molecular level, AF9 mediates transcriptional activation and was classified as a proto-oncogene (9). The AF9 protein interacts with many different factors and has been implicated in different cellular processes (9-11). In the extensive network of interacting proteins, AF9 associates with DOT1L (12, 13), the main enzyme responsible for histone H3 methylation at lysine 79 (14-16). Dot1 is implicated in UV damage repair (17), and affects gene expression in yeast, flies, and mammals (18, 19), whereas histone H3 lysine 79 (H3K79) methylation correlates with gene activation (20) and suppression (21). Following this line, AF9-DOT1L complexes mediate transcriptional activation through increased levels of dimethylated H3K79 (13), but are also capable of transcriptional repression through hypermethyla...

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Cux-2 Controls the Proliferation of Neuronal Intermediate Precursors of the Cortical Subventricular Zone

Cited by 102 publications

References 38 publications

Altered proliferative ability of neuronal progenitors in PlexinA1 mutant mice

Altered proliferative ability of neuronal progenitors in PlexinA1 mutant mice

Possible association of CUX1 gene polymorphisms with antidepressant response in major depressive disorder

Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex

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