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. 2010 Jun;151(6):2443-52.
doi: 10.1210/en.2009-1151. Epub 2010 Apr 14.

Increased expression of angiogenic genes in the brains of mouse meg3-null embryos

Francesca E Gordon  1 , Catherine L Nutt, Pornsuk Cheunsuchon, Yuki Nakayama, Katelyn A Provencher, Kimberley A Rice, Yunli Zhou, Xun Zhang, Anne Klibanski
Affiliations

Increased expression of angiogenic genes in the brains of mouse meg3-null embryos

Francesca E Gordon et al. Endocrinology. 2010 Jun.

Abstract

Maternally expressed gene 3 (MEG3) is a noncoding RNA highly expressed in the normal human brain and pituitary. Expression of MEG3 is lost in gonadotroph-derived clinically nonfunctioning pituitary adenomas. Meg3 knockout mice were generated to identify targets and potential functions of this gene in embryonic development and tumorigenesis. Gene expression profiles were compared in the brains of Meg3-null embryos and wild-type littermate controls using microarray analysis. Microarray data were analyzed with GeneSifter, which uses Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology classifications to identify signaling cascades and functional categories of interest within the dataset. Differences were found in signaling pathways and ontologies related to angiogenesis between wild-type and knockout embryos. Quantitative RT-PCR and immunohistological staining showed increased expression of some Vascular Endothelial Growth Factor pathway genes and increased cortical microvessel density in the Meg3-null embryos. In conclusion, Meg3 may play an important role in control of vascularization in the brain and may function as a tumor suppressor in part by inhibiting angiogenesis.

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Figures

Figure 1
Figure 1
Gene expression measured by quantitative RT-PCR. Expression of Hes1, Vegfa, Vegfr1, and Iqgap1 was determined by quantitative RT-PCR using RNA extracted from the brains of E18.5 embryos collected from eight Meg3-null embryos and seven wild-type (WT) littermates of six litters. KO, Knockout. Values are the mean fold change of quantitative RT-PCR results relative to wild-type. ***, P ≤ 0.005; **, P ≤ 0.01; *, P ≤ 0.05.
Figure 2
Figure 2
Simplified schematic representation of VEGF and Notch signaling cascades showing genes with expression change on the microarray and validated by quantitative RT-PCR. Genes whose increased expression predicted by the microarray analysis was validated by quantitative RT-PCR are represented by dark gray boxes. Light gray boxes denote genes whose increase predicted by microarray analysis approached statistical significance in quantitative RT-PCR assays. Nrp1, represented by a white box, displayed the same direction of change predicted by microarray analysis but did not reach statistical significance. Vegfr2 was not predicted to increase by microarray analysis but was chosen because of the importance of this gene in VEGF signaling. This gene is also denoted by a white box, indicating that the observed increase in expression of this gene was not statistically significant. Black boxes represent other genes that are part of the pathway but not predicted to change with loss of Meg3 by microarray analysis. Solid lines refer to direct interactions and/or effects, and dashed lines refer to indirect action. Arrows denote activation, and perpendicular lines denote repression. FAK, Focal adhesion kinase; Cdc42, cell division control protein 42 homolog; Hey1, Hes-related with YRPW motif 1; CSL, notch-activated coactivator complex of CBF1/Su(H)/Lag2; NICD, Notch intracellular domain.
Figure 3
Figure 3
Representative cortical sections of wild-type (WT) and Meg3-null embryos with Pecam1 and Vegfr2 staining. Pecam1 (A) and Vegfr2 (B) staining of a representative cortical section in a wild-type (left) and a littermate-matched Meg3-null (right) embryo at ×200 magnification. KO, Knockout.
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