How to Build Transcriptional Network Models of Mammalian Pattern Formation

Kioussi, Chrissa; Groß, Michael

doi:10.1371/journal.pone.0002179

Cited by 11 publications

(18 citation statements)

References 45 publications

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“…Total RNA was prepared from forelimbs and probes prepared from these RNA were applied to nine Mouse Genome 430 2.0 microarrays [63]. The results from all nine arrays were normalized by RMA.…”

Section: Methodsmentioning

confidence: 99%

Regulation of Motility of Myogenic Cells in Filling Limb Muscle Anlagen by Pitx2

Campbell

Shih

et al. 2012

PLoS ONE

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Cells of the ventrolateral dermomyotome delaminate and migrate into the limb buds where they give rise to all muscles of the limbs. The migratory cells proliferate and form myoblasts, which withdraw from the cell cycle to become terminally differentiated myocytes. The myogenic lineage colonizes pre-patterned regions to form muscle anlagen as muscle fibers are assembled. The regulatory mechanisms that control the later steps of this myogenic program are not well understood. The homeodomain transcription factor Pitx2 is expressed specifically in the muscle lineage from the migration of precursors to adult muscle. Ablation of Pitx2 results in distortion, rather than loss, of limb muscle anlagen, suggesting that its function becomes critical during the colonization of, and/or fiber assembly in, the anlagen. Microarrays were used to identify changes in gene expression in flow-sorted migratory muscle precursors, labeled by Lbx1EGFP/+, which resulted from the loss of Pitx2. Very few genes showed changes in expression. Many small-fold, yet significant, changes were observed in genes encoding cytoskeletal and adhesion proteins which play a role in cell motility. Myogenic cells from genetically-tagged mice were cultured and subjected to live cell-tracking analysis using time-lapse imaging. Myogenic cells lacking Pitx2 were smaller, more symmetrical, and had more actin bundling. They also migrated about half of the total distance and velocity. Decreased motility may prevent myogenic cells from filling pre-patterned regions of the limb bud in a timely manner. Altered shape may prevent proper assembly of higher-order fibers within anlagen. Pitx2 therefore appears to regulate muscle anlagen development by appropriately balancing expression of cytoskeletal and adhesion molecules.

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Section: Methodsmentioning

confidence: 99%

Regulation of Motility of Myogenic Cells in Filling Limb Muscle Anlagen by Pitx2

Campbell

Shih

et al. 2012

PLoS ONE

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“…Numbers based on 27 drugs selected in the primary phenotypic screen. Six drugs (3,8,10,12,18,24) were eliminated from further analysis by a secondary phenotypic screen. induced pluripotent stem cells.…”

Section: Figurementioning

confidence: 99%

Phenotypic Screening of Drug Library in Actively Differentiating Mouse Embryonic Stem Cells

et al. 2016

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Phenotypic screening enables the discovery of new drug leads with novel targets. ES cells differentiate into different lineages by successively making use of different subsets of the genome's possible macromolecular interactions. If a compound effectively targets just one of these interactions, it derails the developmental pathway to produce a phenotypical change. The OTRADI microsource spectrum library of 2000 approved drug components, natural products, and bioactive components was screened for compounds that can induce phenotypic changes in ES cell cultures at 10 µM after 3 days. Twenty-one compounds that induced specific morphologies also induced unique changes to an expression profile of a dozen markers of early embryonic development, indicating that each compound has derailed the molecular developmental process in a characteristic way. Phenotypic screens conducted with ES cultures differentiating along different lineages can be used to efficiently prescreen compounds able to regulate cell differentiation lineage.

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“…Scatter plot comparisons of individual arrays showed fewer changes in internal comparisons, between replicate arrays from the same genotype, than in cross comparisons, between individual arrays from different genotypes (data not shown). The number of regulated genes can be estimated by permutation fold-scanning analysis (28,29). This non-parametric method counts probe set comparisons that fall above each -fold cutoff between conditions (cross comparisons) and within conditions (internal comparisons) and uses them to calculate the number of regulated genes as a function of -fold change or false discovery rate (FDR) (29,30).…”

Section: Identification Of T-box Genes Regulated By Pitx2 In Abdomi-mentioning

confidence: 99%

“…The number of regulated genes can be estimated by permutation fold-scanning analysis (28,29). This non-parametric method counts probe set comparisons that fall above each -fold cutoff between conditions (cross comparisons) and within conditions (internal comparisons) and uses them to calculate the number of regulated genes as a function of -fold change or false discovery rate (FDR) (29,30). An FDR of 8% was calculated for WT versus MUT comparisons at a 1.7-fold cutoff.…”

Section: Identification Of T-box Genes Regulated By Pitx2 In Abdomi-mentioning

confidence: 99%

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Pitx2-dependent Occupancy by Histone Deacetylases Is Associated with T-box Gene Regulation in Mammalian Abdominal Tissue

Hilton

Groß

Kioussi

2010

Journal of Biological Chemistry

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The homeodomain transcription factor Pitx2 and the T-box transcription factors are essential for organogenesis. Pitx2 and T-box genes are induced by growth factors and function as transcriptional activators or repressors. Gene expression analyses on abdominal tissue were used to identify seven of the T-box genes of the genome as Pitx2 target genes in the abdomen at embryonic day.10.5. Pitx2 activated Tbx4, Tbx15, and Mga and repressed Tbx1, Tbx2, Tbx5, and Tbx6 expression. As expected, activated genes showed reduced expression patterns, and repressed T-box genes showed increased expression patterns in the abdomen of Pitx2 mutants. Pitx2 occupied chromatin sites near all of these T-box genes. Co-occupancy by coactivators, corepressors, and histone acetylation at these sites was frequently Pitx2-dependent. Genes repressed by Pitx2 generally showed increased histone acetylation and decreased histone deacetylase (HDAC)/corepressor occupancy in Pitx2 mutants. The lower N-CoR, HDAC1, and HDAC3 occupancy observed at multiple sites along Tbx1 chromatin in mutants is consistent with the model that increased histone acetylation and gene expression of Tbx1 may result from a loss of recruitment of corepressors by Pitx2. Genes activated by Pitx2 showed less consistent patterns in chromatin analyses. Reduced H4 acetylation and increased HDAC1/nuclear receptor corepressor (N-CoR) occupancy at some Tbx4 sites were accompanied by increased H3 acetylation and reduced HDAC3 occupancy at the same or other more distal chromatin sites in mutants. Pitx2-dependent occupancy by corepressors resulted in alteration of the acetylation levels of several T-box genes, whereas Pitx2-dependent occupancy by coactivators was more site-localized. These studies will provide the basic scientific underpinning to understand abdominal wall syndromes.Definitive endoderm and lateral plate mesoderm cells are formed and begin to migrate laterally between the ectoderm and primitive endoderm during early gastrulation. Together, these cells form the abdominal wall that begins to enclose the internal organs shortly after the mouse embryo turns. The abdominal wall at mouse embryonic day (E) 3 9.5 is composed of lateral plate mesoderm-derived mesenchymal cells inserted between ectoderm-and endoderm-derived cell layers. Abdominal somites are beginning to extend ventrally into the lateral plate-derived mesenchyme to form abdominal wall muscle anlagen. Classic ventral body wall defects are characterized by a thin body wall, muscular dysplasia, and/or absence of midline fusion (1, 2).Several sequence-specific DNA binding transcription factors (SSTFs) are involved in the pathogenesis of congenital body wall defects. These include the homeodomain transcription factor Pitx2, which is essential for organ formation and body wall closure (3-6). Pitx2 is a target of growth factor signaling pathways that mediate cell type-specific control of proliferation. Activation of the Wnt/␤-catenin pathway results in the release of Pitx2-associated corepressors and mediates recruitmen...

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How to Build Transcriptional Network Models of Mammalian Pattern Formation

Cited by 11 publications

References 45 publications

Regulation of Motility of Myogenic Cells in Filling Limb Muscle Anlagen by Pitx2

Regulation of Motility of Myogenic Cells in Filling Limb Muscle Anlagen by Pitx2

Phenotypic Screening of Drug Library in Actively Differentiating Mouse Embryonic Stem Cells

Pitx2-dependent Occupancy by Histone Deacetylases Is Associated with T-box Gene Regulation in Mammalian Abdominal Tissue

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