Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Identification of immediate early transcriptional targets of ephrin-B1 forward signaling

ABSTRACT: The goal of this study was to identify immediate early transcriptional targets of ephrin-B1 forward signaling that are relevant to palatogenesis. The Ephs compose a family of receptor tyrosine kinase signaling molecules that can be activated by their cognate ligands, the ephrins. Despite the importance of Eph/ephrin signaling in a wide variety of developmental and cell biological processes, a potential downstream transcriptional response has not been explored. To understand the role of ephrin-B1 signaling in palatogenesis, we examined transcriptional response to ephrin-B1 in a primary mouse embryonic palatal shelf cell culture system. We find an immediate early signature of gene expression that reflects the activation of Erk/MAPK signaling by ephrin-B1 signaling in the palatal shelves. Induction of primary palate cells with 2 ug/ml of pre-clustered ephrin-B1 for one hour. Uninduced primary palate cells are the control. Four replicates each.

ORGANISM(S): Mus musculus

SUBMITTER: Jeffrey Bush

PROVIDER: E-GEOD-23539 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Ephrin-B1 forward signaling regulates craniofacial morphogenesis by controlling cell proliferation across Eph-ephrin boundaries.

Bush Jeffrey O JO Soriano Philippe P

Genes & development 20100901 18

Mutations in the X-linked human EPHRIN-B1 gene result in cleft palate and other craniofacial anomalies as part of craniofrontonasal syndrome (CFNS), but the molecular and developmental mechanisms by which ephrin-B1 controls the underlying developmental processes are not clear. Here we demonstrate that ephrin-B1 plays an intrinsic role in palatal shelf outgrowth in the mouse by regulating cell proliferation in the anterior palatal shelf mesenchyme. In ephrin-B1 heterozygous mutants, X inactivatio ...[more]

PMID: 20844017

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Project description:Background: In humans, cleft palate (CP) accounts for one of the largest number of birth defects with a complex genetic and environmental etiology. TGFM-NM-23 has been established as an important regulator of palatal fusion in mice and it has been shown that TGFM-NM-23-null mice exhibit CP without any other major deformities. However, the genes that regulate cellular decisions and molecular mechanisms maintained by the TGFM-NM-23 pathway throughout palatogenesis are predominantly unexplored. Our objective in this study was to analyze global transcriptome changes within the palate during different gestational ages within TGFM-NM-23 knockout mice to identify TGFM-NM-23-associated genes previously unknown to be associated with the development of cleft palate. We used deep sequencing technology, RNA-Seq, to analyze the transcriptome of TGFM-NM-23 knockout mice at crucial stages of palatogenesis, including palatal growth (E14.5), adhesion (E15.5), and fusion (E16.5). Results: The overall transcriptome analysis of TGFM-NM-23 wildtype mice (C57BL/6) reveals that almost 6000 genes were upregulated during the transition from E14.5 to E15.5 and more than 2000 were downregulated from E15.5 to E16.5. Using bioinformatics tools and databases, we identified the most comprehensive list of CP genes (n = 322) in which mutations cause CP either in humans or mice, and analyzed their expression patterns. The expression motifs of CP genes between TGFM-NM-23+/M-bM-^HM-^R and TGFM-NM-23M-bM-^HM-^R/M-bM-^HM-^R were not significantly different from each other, and the expression of the majority of CP genes remained unchanged from E14.5 to E16.5. Using these patterns, we identified 8 unique genes within TGFM-NM-23M-bM-^HM-^R/M-bM-^HM-^R mice (Chrng Foxc2, H19, Kcnj13, Lhx8, Meox2, Shh, and Six3), which may function as the primary contributors to the development of cleft palate in TGFM-NM-23M-bM-^HM-^R/M-bM-^HM-^R mice. When the significantly altered CP genes were overlaid with TGFM-NM-2 signaling, all of these genes followed the Smad-dependent pathway. Conclusions: Our study represents the first analysis of the palatal transcriptome of the mouse, as well as TGFM-NM-23 knockout mice, using deep sequencing methods. In this study, we characterized the critical regulation of palatal transcripts that may play key regulatory roles through crucial stages of palatal development. We identified potential causative CP genes in a TGFM-NM-23 knockout model, which may lead to a better understanding of the genetic mechanisms of palatogenesis and provide novel potential targets for gene therapy approaches to treat cleft palate. Palatal mRNA profiles of wild type (WT), TGFM-NM-23+/-, and TGFM-NM-23-/- mice at E14.5, E15.5, and E16.5 were generated by deep sequencing, in triplicate, using Illumina HiSeq2000

Project description:Background: In humans, cleft palate (CP) accounts for one of the largest number of birth defects with a complex genetic and environmental etiology. TGFβ3 has been established as an important regulator of palatal fusion in mice and it has been shown that TGFβ3-null mice exhibit CP without any other major deformities. However, the genes that regulate cellular decisions and molecular mechanisms maintained by the TGFβ3 pathway throughout palatogenesis are predominantly unexplored. Our objective in this study was to analyze global transcriptome changes within the palate during different gestational ages within TGFβ3 knockout mice to identify TGFβ3-associated genes previously unknown to be associated with the development of cleft palate. We used deep sequencing technology, RNA-Seq, to analyze the transcriptome of TGFβ3 knockout mice at crucial stages of palatogenesis, including palatal growth (E14.5), adhesion (E15.5), and fusion (E16.5). Results: The overall transcriptome analysis of TGFβ3 wildtype mice (C57BL/6) reveals that almost 6000 genes were upregulated during the transition from E14.5 to E15.5 and more than 2000 were downregulated from E15.5 to E16.5. Using bioinformatics tools and databases, we identified the most comprehensive list of CP genes (n = 322) in which mutations cause CP either in humans or mice, and analyzed their expression patterns. The expression motifs of CP genes between TGFβ3+/− and TGFβ3−/− were not significantly different from each other, and the expression of the majority of CP genes remained unchanged from E14.5 to E16.5. Using these patterns, we identified 8 unique genes within TGFβ3−/− mice (Chrng Foxc2, H19, Kcnj13, Lhx8, Meox2, Shh, and Six3), which may function as the primary contributors to the development of cleft palate in TGFβ3−/− mice. When the significantly altered CP genes were overlaid with TGFβ signaling, all of these genes followed the Smad-dependent pathway. Conclusions: Our study represents the first analysis of the palatal transcriptome of the mouse, as well as TGFβ3 knockout mice, using deep sequencing methods. In this study, we characterized the critical regulation of palatal transcripts that may play key regulatory roles through crucial stages of palatal development. We identified potential causative CP genes in a TGFβ3 knockout model, which may lead to a better understanding of the genetic mechanisms of palatogenesis and provide novel potential targets for gene therapy approaches to treat cleft palate.

Dataset Information

Identification of immediate early transcriptional targets of ephrin-B1 forward signaling

Publications

Ephrin-B1 forward signaling regulates craniofacial morphogenesis by controlling cell proliferation across Eph-ephrin boundaries.

Similar Datasets

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