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Major transcriptome re-organisation and abrupt changes in signalling, cell cycle and chromatin regulation at neural differentiation in vivo.

Olivera-Martinez I, Schurch N, Li RA, Song J, Halley PA, Das RM, Burt DW, Barton GJ, Storey KG - Development (2014)

Bottom Line: We show that these changes are conserved across species and provide biological evidence for reduced proteasome efficiency and a novel lengthening of S phase.We further demonstrate that transcription of one such gene, HDAC1, is dependent on FGF signalling, making a novel link between signals that control neural differentiation and transcription of a core regulator of chromatin organisation.Our work implicates new signalling pathways and dynamics, cellular processes and epigenetic modifiers in neural differentiation in vivo, identifying multiple new potential cellular and molecular mechanisms that direct differentiation.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.

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KEGG pathway gene expression profiles along the neural axis. (A-F) KEGG pathways whose gene annotations are significantly over-represented within the list of genes identified as significantly differentially expressed between SZ+PNT and CNT+RNT. Upper half of each panel shows expression profiles of genes upregulated; lower half shows genes downregulated across the ‘differentiation switch’. The value plotted on the y-axis is log2 relative expression, scaled to the mean expression of that gene across all tissues. This represents the fractional change, rather than the absolute change, in expression level across the switch; highly expressed genes may show statistically significant differential expression even for small changes in relative expression. Profiles shown with solid lines were annotated to the pathway within the ‘chicken.db’ R package (and thus represent the set that the enrichment test is performed against); those with dotted lines were manually assigned from the lists of statistically significantly regulated genes. (A) MAPK pathway; (B) Wnt pathways; (C) steroid biosynthesis pathway; (D) Hedgehog pathway (note that KEGG annotates some Wnt pathway genes to the Hedgehog pathway); (E) TGFβ pathway; (F) Notch pathway.
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DEV112623F4: KEGG pathway gene expression profiles along the neural axis. (A-F) KEGG pathways whose gene annotations are significantly over-represented within the list of genes identified as significantly differentially expressed between SZ+PNT and CNT+RNT. Upper half of each panel shows expression profiles of genes upregulated; lower half shows genes downregulated across the ‘differentiation switch’. The value plotted on the y-axis is log2 relative expression, scaled to the mean expression of that gene across all tissues. This represents the fractional change, rather than the absolute change, in expression level across the switch; highly expressed genes may show statistically significant differential expression even for small changes in relative expression. Profiles shown with solid lines were annotated to the pathway within the ‘chicken.db’ R package (and thus represent the set that the enrichment test is performed against); those with dotted lines were manually assigned from the lists of statistically significantly regulated genes. (A) MAPK pathway; (B) Wnt pathways; (C) steroid biosynthesis pathway; (D) Hedgehog pathway (note that KEGG annotates some Wnt pathway genes to the Hedgehog pathway); (E) TGFβ pathway; (F) Notch pathway.

Mentions: The genes most highly expressed in stem zone in comparison with preneural tube included multiple pathways that were newly implicated in the regulation of this cell population: (1) GFRA1 (glial-derived nerve growth factor receptor), NGF-induced gene EGR1/KROX24, UNC5B/NETRIN1 receptor and EPHA1, which are normally associated with cell adhesion and axon guidance; (2) steroid hormone signalling, indicated by elevated GREB1 expression (gene regulated by oestrogen in breast cancer 1), a target of oestrogen and androgen receptors that also has 5′ binding sites for glucocorticoid and progesterone receptors (Rae et al., 2006; Deschenes et al., 2007) (validated by in situ hybridisation in supplementary material Fig. S1 and see below); (3) PDGFR-alpha, which is implicated in cell proliferation, survival and chemotaxis; and (4) CD3-epsilon, an immunoglobulin superfamily member and a constituent of the T cell receptor (Kuhns and Badgandi, 2012). KEGG analysis essentially confirmed the representation of two known signalling pathways, FGF/MAPK and Wnt (Fig. 3A,B; Fig. 4A,B). Consistent with co-expression of mesoderm and neural progenitor genes in the stem zone, representative transcription factors included mesodermal genes T (brachyury), cNOT2 and gNOT1. Genes expressed highly in the PNT in comparison with the SZ are involved in a distinct set of signalling pathways: potassium and magnesium ion channel genes; fatty acid binding proteins (e.g. FABP5 validated by in situ hybridisation in supplementary material Fig. S1) linked to PPARβ/δ and retinoid signalling; VEGFR3; and the first expression of Shh receptor PTCH1 and associated ventral patterning transcription factors NKX6.1 and NKX6.2.Fig. 3.


Major transcriptome re-organisation and abrupt changes in signalling, cell cycle and chromatin regulation at neural differentiation in vivo.

Olivera-Martinez I, Schurch N, Li RA, Song J, Halley PA, Das RM, Burt DW, Barton GJ, Storey KG - Development (2014)

KEGG pathway gene expression profiles along the neural axis. (A-F) KEGG pathways whose gene annotations are significantly over-represented within the list of genes identified as significantly differentially expressed between SZ+PNT and CNT+RNT. Upper half of each panel shows expression profiles of genes upregulated; lower half shows genes downregulated across the ‘differentiation switch’. The value plotted on the y-axis is log2 relative expression, scaled to the mean expression of that gene across all tissues. This represents the fractional change, rather than the absolute change, in expression level across the switch; highly expressed genes may show statistically significant differential expression even for small changes in relative expression. Profiles shown with solid lines were annotated to the pathway within the ‘chicken.db’ R package (and thus represent the set that the enrichment test is performed against); those with dotted lines were manually assigned from the lists of statistically significantly regulated genes. (A) MAPK pathway; (B) Wnt pathways; (C) steroid biosynthesis pathway; (D) Hedgehog pathway (note that KEGG annotates some Wnt pathway genes to the Hedgehog pathway); (E) TGFβ pathway; (F) Notch pathway.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4197544&req=5

DEV112623F4: KEGG pathway gene expression profiles along the neural axis. (A-F) KEGG pathways whose gene annotations are significantly over-represented within the list of genes identified as significantly differentially expressed between SZ+PNT and CNT+RNT. Upper half of each panel shows expression profiles of genes upregulated; lower half shows genes downregulated across the ‘differentiation switch’. The value plotted on the y-axis is log2 relative expression, scaled to the mean expression of that gene across all tissues. This represents the fractional change, rather than the absolute change, in expression level across the switch; highly expressed genes may show statistically significant differential expression even for small changes in relative expression. Profiles shown with solid lines were annotated to the pathway within the ‘chicken.db’ R package (and thus represent the set that the enrichment test is performed against); those with dotted lines were manually assigned from the lists of statistically significantly regulated genes. (A) MAPK pathway; (B) Wnt pathways; (C) steroid biosynthesis pathway; (D) Hedgehog pathway (note that KEGG annotates some Wnt pathway genes to the Hedgehog pathway); (E) TGFβ pathway; (F) Notch pathway.
Mentions: The genes most highly expressed in stem zone in comparison with preneural tube included multiple pathways that were newly implicated in the regulation of this cell population: (1) GFRA1 (glial-derived nerve growth factor receptor), NGF-induced gene EGR1/KROX24, UNC5B/NETRIN1 receptor and EPHA1, which are normally associated with cell adhesion and axon guidance; (2) steroid hormone signalling, indicated by elevated GREB1 expression (gene regulated by oestrogen in breast cancer 1), a target of oestrogen and androgen receptors that also has 5′ binding sites for glucocorticoid and progesterone receptors (Rae et al., 2006; Deschenes et al., 2007) (validated by in situ hybridisation in supplementary material Fig. S1 and see below); (3) PDGFR-alpha, which is implicated in cell proliferation, survival and chemotaxis; and (4) CD3-epsilon, an immunoglobulin superfamily member and a constituent of the T cell receptor (Kuhns and Badgandi, 2012). KEGG analysis essentially confirmed the representation of two known signalling pathways, FGF/MAPK and Wnt (Fig. 3A,B; Fig. 4A,B). Consistent with co-expression of mesoderm and neural progenitor genes in the stem zone, representative transcription factors included mesodermal genes T (brachyury), cNOT2 and gNOT1. Genes expressed highly in the PNT in comparison with the SZ are involved in a distinct set of signalling pathways: potassium and magnesium ion channel genes; fatty acid binding proteins (e.g. FABP5 validated by in situ hybridisation in supplementary material Fig. S1) linked to PPARβ/δ and retinoid signalling; VEGFR3; and the first expression of Shh receptor PTCH1 and associated ventral patterning transcription factors NKX6.1 and NKX6.2.Fig. 3.

Bottom Line: We show that these changes are conserved across species and provide biological evidence for reduced proteasome efficiency and a novel lengthening of S phase.We further demonstrate that transcription of one such gene, HDAC1, is dependent on FGF signalling, making a novel link between signals that control neural differentiation and transcription of a core regulator of chromatin organisation.Our work implicates new signalling pathways and dynamics, cellular processes and epigenetic modifiers in neural differentiation in vivo, identifying multiple new potential cellular and molecular mechanisms that direct differentiation.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.

Show MeSH
Related in: MedlinePlus