Unknown,Transcriptomics,Genomics,Proteomics

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The Poly(C) binding protein Pcbp2, and its retrotransposed derivative Pcbp1, are independently essential to mouse development

ABSTRACT: RNA-binding proteins participate in a complex array of post-transcriptional controls essential to cell-type specification and somatic development. Despite their detailed biochemical characterizations, the degree to which each RNA-binding protein impacts on mammalian embryonic development remains incompletely defined and the level of functional redundancy among subsets of these proteins remains open to question. The poly-(C) binding proteins, Pcbp's (aCPs, hnRNPEs), are encoded by a highly conserved and broadly expressed gene family. The two major Pcbp isoforms, Pcbp2 and Pcbp1, are robustly expressed in a wide range of tissues and exert both nuclear and cytoplasmic controls over gene expression. Here we report that Pcbp1-null embryos are rendered nonviable in the peri-implantation stage. In contrast, Pcbp2-null embryos survive until mid-gestation at which time they undergo a loss in viability associated with cardiovascular and hematopoietic abnormalities. Adult mice heterozygous for either Pcbp1 or Pcbp2 null alleles display a mild and non-disruptive growth defect. These data reveal that Pcbp1 and Pcbp2 are individually essential for mouse embryonic development and post-natal growth, reveal a non-redundant in vivo role for Pcpb2 in hematopoiesis, and provide direct evidence that Pcbp1, a retrotransposed derivative of Pcpb2, has evolved essential function(s) in the mammalian genome. mRNA-seq on fetal liver tissue from 12.5 days post coitum. 4 replicates of WT and 3 replicates of PCBP2 Knockout

ORGANISM(S): Mus musculus

SUBMITTER: Ian Silverman

PROVIDER: E-GEOD-72491 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The Poly(C) Binding Protein Pcbp2 and Its Retrotransposed Derivative Pcbp1 Are Independently Essential to Mouse Development.

Ghanem Louis R LR Kromer Andrew A Silverman Ian M IM Chatterji Priya P Traxler Elizabeth E Penzo-Mendez Alfredo A Weiss Mitchell J MJ Stanger Ben Z BZ Liebhaber Stephen A SA

Molecular and cellular biology 20151102 2

RNA-binding proteins participate in a complex array of posttranscriptional controls essential to cell type specification and somatic development. Despite their detailed biochemical characterizations, the degree to which each RNA-binding protein impacts mammalian embryonic development remains incompletely defined, and the level of functional redundancy among subsets of these proteins remains open to question. The poly(C) binding proteins, PCBPs (αCPs and hnRNP E proteins), are encoded by a highly ...[more]

PMID: 26527618

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Project description:Mutations in methyl-CpG-binding protein 2 (MeCP2), a major epigenetic regulator, are the predominant cause of Rett syndrome, an X-linked neurodevelopmental disorder. We previously found that Mecp2-null microglia are functionally impaired, and that engraftment of wild-type monocytes into the brain of Mecp2-deficient mice attenuates pathology. In this study we show that Mecp2 is expressed in macrophage and monocyte populations throughout the body, and is indispensable for their transcriptional regulation in multiple contexts. We demonstrate that Mecp2-null mice progressively lose or are chronically deficient in several macrophage populations and resident monocytes. Postnatal re-expression of Mecp2 driven by a tamoxifen-inducible CX3CR1 promoter significantly increased the lifespan of otherwise Mecp2-null mice, suggesting that epigenetic regulation of macrophage function by Mecp2 significantly contributes to pathology. RNA-Seq of acutely isolated microglia and peritoneal macrophages (to our knowledge, the first cell-specific RNA-Seq analysis comparing Mecp2-null and wild type cells of any kind) revealed significantly increased transcription of glucocorticoid- and hypoxia-signaling genes in Mecp2-null cells compared to that in their wild-type counterparts, suggesting that Mecp2 functions as a repressor of these pathways. Furthermore, in-vitro and in vivo validation studies demonstrated that the absence of Mecp2 is associated with cell-intrinsic dysfunction of signaling underlying inflammatory activation, suggesting that Mecp2 is important for regulation of specific macrophage gene-expression programs in response to stimuli and stressors. Our findings demonstrate a fundamental role for Mecp2 in the regulation of macrophage functions, which may provide a link to pathologies in Rett syndrome across multiple organs. Mecp2-null microglia and resident peritoneal macrophages from 10-12 week old mice were acutely isolated via AutoMACS, total RNA collected, and analyzed via RNA-Seq to compare for transcriptional differences in microglia and macrophages in the absence of Mecp2.

Dataset Information

The Poly(C) binding protein Pcbp2, and its retrotransposed derivative Pcbp1, are independently essential to mouse development

Publications

The Poly(C) Binding Protein Pcbp2 and Its Retrotransposed Derivative Pcbp1 Are Independently Essential to Mouse Development.

Similar Datasets

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