Transcriptome signature of the adult mouse choroid plexus

Marques, Fernanda; Sousa, João Carlos; Coppola, Giovanni; Gao, Fuying; Puga, Renato; Brentani, Helena; Geschwind, Daniel H.; Sousa, Nuno; Correia-Neves, Margarida; Palha, Joana Almeida

doi:10.1186/2045-8118-8-10

Cited by 85 publications

(104 citation statements)

References 34 publications

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“…S4) grouped the samples according to their genotype. Reassuringly, genes already known to be highly expressed in the ChP, such as the very abundant Ttr, Igf and Aqp1 mRNAs (Lehtinen et al, 2011;Marques et al, 2011), were also highly expressed in the current analysis. Indeed, Ttr is the second most abundant mRNA in E13 control ChP and is similarly abundant in the mutant ChP, suggesting that our dissection procedure was successful in isolating the remnant ChP and that no major change in composition of the ChP was evident.…”

Section: Transcriptome Analysis Of Hindbrain Chp Reveals Major Alteramentioning

confidence: 83%

The transcription factor Otx2 regulates choroid plexus development and function

et al. 2013

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SUMMARYThe choroid plexuses (ChPs) are the main regulators of cerebrospinal fluid (CSF) composition and thereby also control the composition of a principal source of signaling molecules that is in direct contact with neural stem cells in the developing brain. The regulators of ChP development mediating the acquisition of a fate that differs from the neighboring neuroepithelial cells are poorly understood. Here, we demonstrate in mice a crucial role for the transcription factor Otx2 in the development and maintenance of ChP cells. Deletion of Otx2 by the Otx2-CreERT2 driver line at E9 resulted in a lack of all ChPs, whereas deletion by the Gdf7-Cre driver line affected predominately the hindbrain ChP, which was reduced in size, primarily owing to an increase in apoptosis upon Otx2 deletion. Strikingly, Otx2 was still required for the maintenance of hindbrain ChP cells at later stages when Otx2 deletion was induced at E15, demonstrating a central role of Otx2 in ChP development and maintenance. Moreover, the predominant defects in the hindbrain ChP mediated by Gdf7-Cre deletion of Otx2 revealed its key role in regulating early CSF composition, which was altered in protein content, including the levels of Wnt4 and the Wnt modulator Tgm2. Accordingly, proliferation and Wnt signaling levels were increased in the distant cerebral cortex, suggesting a role of the hindbrain ChP in regulating CSF composition, including key signaling molecules. Thus, Otx2 acts as a master regulator of ChP development, thereby influencing one of the principal sources of signaling in the developing brain, the CSF.

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Section: Transcriptome Analysis Of Hindbrain Chp Reveals Major Alteramentioning

confidence: 83%

The transcription factor Otx2 regulates choroid plexus development and function

et al. 2013

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“…BMP9 mRNA is expressed in multiple brain regions of adult mice [Gene Expression Omnibus (GEO) accession GDS592] and humans (GEO accession GDS596) (59); however, the exact cell types producing BMP9 in brain remain to be determined. Choroid plexus also expresses multiple BMPs (including BMP9) (60) and is a source of these proteins in the cerebrospinal fluid (61). Although there are no data on the levels of BMP9 in AD brain, there is a single report indicating that the levels of a related protein, BMP6 (but not BMP2 and BMP7), are increased in the hippocampus of AD patients and in a mouse AD model (62).…”

Section: Discussionmentioning

confidence: 99%

BMP9 ameliorates amyloidosis and the cholinergic defect in a mouse model of Alzheimer’s disease

Burke¹,

Norman²,

Haydar

et al. 2013

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

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Bone morphogenetic protein 9 (BMP9) promotes the acquisition of the cholinergic phenotype in basal forebrain cholinergic neurons (BFCN) during development and protects these neurons from cholinergic dedifferentiation following axotomy when administered in vivo. A decline in BFCN function occurs in patients with Alzheimer's disease (AD) and contributes to the AD-associated memory deficits. We infused BMP9 intracerebroventricularly for 7 d in transgenic AD model mice expressing green fluorescent protein specifically in cholinergic neurons (APP.PS1/CHGFP) and in wild-type littermate controls (WT/CHGFP). We used 5-mo-old mice, an age when the AD transgenics display early amyloid deposition and few cholinergic defects, and 10-mo-old mice, by which time these mice exhibit established disease. BMP9 infusion reduced the number of Aβ42-positive amyloid plaques in the hippocampus and cerebral cortex of 5-and 10-mo-old APP.PS1/CHGFP mice and reversed the reductions in choline acetyltransferase protein levels in the hippocampus of 10-mo-old APP.PS1/CHGFP mice. The treatment increased cholinergic fiber density in the hippocampus of both WT/CHGFP and APP.PS1/CHGFP mice at both ages. BMP9 infusion also increased hippocampal levels of neurotrophin 3, insulin-like growth factor 1, and nerve growth factor and of the nerve growth factor receptors, tyrosine kinase receptor A and p75/NGFR, irrespective of the genotype of the mice. These data show that BMP9 administration is effective in reducing the Aβ42 amyloid plaque burden, reversing cholinergic neuron abnormalities, and generating a neurotrophic milieu for BFCN in a mouse model of AD and provide evidence that the BMP9-signaling pathway may constitute a therapeutic target for AD.acetylcholine | APPswe PS1dE9 mice | growth/differentiation factor 2 | juvenile protective factors B asal forebrain cholinergic neurons (BFCN) project to the hippocampus and cerebral cortex where the release of their neurotransmitter, acetylcholine (ACh), is central for the processes of learning, memory, and attention throughout life (1). The acquisition of the cholinergic phenotype by these neurons during development is induced by bone morphogenetic protein 9 (BMP9), also known as growth/differentiation factor 2 (GDF2), which is expressed in the fetal basal forebrain (2). Application of BMP9 to basal forebrain cell cultures and into the cerebral ventricles of developing mouse embryos (2) and adult mice (3) significantly increases ACh production. Moreover, the idea that the BMP9-signaling pathway may be a master regulator of the BFCN phenotype is supported by evidence showing that BMP9 is sufficient to induce BFCN-like features in human embryonic stem cell-derived neural progenitor cells (4) and that, in rodent basal forebrain cell cultures, BMP9 induces the BFCN transcriptome (5). Recent studies indicate that intracerebroventricularly (i.c.v.)-infused BMP9 fully prevents the cholinergic dedifferentiation (i.e., loss of cholinergic markers) of axotomized BFCN in mice (3). Taken together, these data provid...

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“…Hem ablation had less obvious effects on indicators of BMP signaling, possibly because BMP ligands are secreted by choroid plexus epithelium (CPe), and are available to ventricular zone (VZ) progenitor cells from embryonic cerebrospinal fluid (Lehtinen and Walsh, 2011;Marques et al, 2011). Lack of WNT signaling from the hem caused loss of the adjacent hippocampus, whereas lack of hem BMPs only reduced the adjacent CPe (Yoshida et al, 2006).…”

Section: Reduced Indicators Of Wnt and Bmp Signaling In Hemablated Micementioning

confidence: 99%

The cortical hem regulates the size and patterning of neocortex

et al. 2014

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The cortical hem, a source of Wingless-related (WNT) and bone morphogenetic protein (BMP) signaling in the dorsomedial telencephalon, is the embryonic organizer for the hippocampus. Whether the hem is a major regulator of cortical patterning outside the hippocampus has not been investigated. We examined regional organization across the entire cerebral cortex in mice genetically engineered to lack the hem. Indicating that the hem regulates dorsoventral patterning in the cortical hemisphere, the neocortex, particularly dorsomedial neocortex, was reduced in size in latestage hem-ablated embryos, whereas cortex ventrolateral to the neocortex expanded dorsally. Unexpectedly, hem ablation also perturbed regional patterning along the rostrocaudal axis of neocortex. Rostral neocortical domains identified by characteristic gene expression were expanded, and caudal domains diminished. A similar shift occurs when fibroblast growth factor (FGF) 8 is increased at the rostral telencephalic organizer, yet the FGF8 source was unchanged in hem-ablated brains. Rather we found that hem WNT or BMP signals, or both, have opposite effects to those of FGF8 in regulating transcription factors that control the size and position of neocortical areas. When the hem is ablated a necessary balance is perturbed, and cerebral cortex is rostralized. Our findings reveal a much broader role for the hem in cortical development than previously recognized, and emphasize that two major signaling centers interact antagonistically to pattern cerebral cortex.

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Transcriptome signature of the adult mouse choroid plexus

Cited by 85 publications

References 34 publications

The transcription factor Otx2 regulates choroid plexus development and function

The transcription factor Otx2 regulates choroid plexus development and function

BMP9 ameliorates amyloidosis and the cholinergic defect in a mouse model of Alzheimer’s disease

The cortical hem regulates the size and patterning of neocortex

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