Tbx2 Terminates Shh/Fgf Signaling in the Developing Mouse Limb Bud by Direct Repression of Gremlin1

Farin, Henner F.; Lüdtke, Timo H.-W.; Schmidt, Martina K.; Placzko, Susann; Schuster-Gossler, Karin; Petry, Marianne; Christoffels, Vincent M.; Kispert, Andreas

doi:10.1371/journal.pgen.1003467

Cited by 49 publications

(49 citation statements)

References 58 publications

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“…These apparent similarities in cis -regulation are likely related to the emergence of these gene clusters by duplication of an ancestral complex (Agulnik et al, 1996). Genetic and overexpression analysis has previously implicated Tbx3 in early forelimb development together with Hand2 and Gli3 (Davenport et al, 2003; Rallis et al, 2005), while Tbx2 is essential only during termination of limb bud outgrowth (Farin et al, 2013). Therefore, we focused our analysis on the HAND2-TBX3 interactions during the onset of forelimb bud development.…”

Section: Resultsmentioning

confidence: 99%

HAND2 Targets Define a Network of Transcriptional Regulators that Compartmentalize the Early Limb Bud Mesenchyme

et al. 2014

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Summary The genetic networks that govern vertebrate development are well studied, but how the interactions of trans-acting factors with cis-regulatory modules (CRMs) are integrated into spatio-temporal regulation of gene expression is not clear. The transcriptional regulator HAND2 is required during limb, heart and branchial arch development. Here, we identify the genomic regions enriched in HAND2 chromatin complexes from mouse embryos and limb buds. Then, we analyze the HAND2 target CRMs in the genomic landscapes encoding transcriptional regulators required in early limb buds. HAND2 controls the expression of genes functioning in the proximal limb bud and orchestrates the establishment of anterior and posterior polarity of the nascent limb bud mesenchyme by impacting on Gli3 and Tbx3 expression. TBX3 is required downstream of HAND2 to refine the posterior Gli3 expression boundary. Our analysis uncovers the transcriptional circuits that function in establishing distinct mesenchymal compartments downstream of HAND2 and upstream of SHH signaling.

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Section: Resultsmentioning

confidence: 99%

HAND2 Targets Define a Network of Transcriptional Regulators that Compartmentalize the Early Limb Bud Mesenchyme

et al. 2014

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“…This may result in the differential expression of Homeobox genes or T-box genes, which are body axis organizers that can potentially regulate GREM1 expression343536. Additionally, RA signalling can be swiftly modulated during feather growth to give rise to abrupt vane shape changes like emarginated notches.…”

Section: Discussionmentioning

confidence: 99%

Diverse feather shape evolution enabled by coupling anisotropic signalling modules with self-organizing branching programme

Figueroa

Jiang

et al. 2017

Nat Commun

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Adaptation of feathered dinosaurs and Mesozoic birds to new ecological niches was potentiated by rapid diversification of feather vane shapes. The molecular mechanism driving this spectacular process remains unclear. Here, through morphology analysis, transcriptome profiling, functional perturbations and mathematical simulations, we find that mesenchyme-derived GDF10 and GREM1 are major controllers for the topologies of rachidial and barb generative zones (setting vane boundaries), respectively, by tuning the periodic-branching programme of epithelial progenitors. Their interactions with the anterior–posterior WNT gradient establish the bilateral-symmetric vane configuration. Additionally, combinatory effects of CYP26B1, CRABP1 and RALDH3 establish dynamic retinoic acid (RA) landscapes in feather mesenchyme, which modulate GREM1 expression and epithelial cell shapes. Incremental changes of RA gradient slopes establish a continuum of asymmetric flight feathers along the wing, while switch-like modulation of RA signalling confers distinct vane shapes between feather tracts. Therefore, the co-option of anisotropic signalling modules introduced new dimensions of feather shape diversification.

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“…In addition, the descendants of SHH-producing cells do not express Grem1 (Scherz et al, 2004). Grem1 is also repressed by direct transcriptional inputs from GLI3 and TBX2 in the anterior and posterior margins of the limb, respectively (Farin et al, 2013; Li et al, 2014; Litingtung et al, 2002; te Welscher et al, 2002; Vokes et al, 2008). …”

Section: Introductionmentioning

confidence: 99%

Dynamics of BMP signaling in limb bud mesenchyme and polydactyly

Norrie

Lewandowski

Bouldin³

et al. 2014

Developmental Biology

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Mutations in the Bone Morphogenetic Protein (BMP) pathway are associated with a range of defects in skeletal formation. Genetic analysis of BMP signaling requirements is complicated by the presence of three partially redundant BMPs that are required for multiple stages of limb development. We generated an inducible allele of a BMP inhibitor, Gremlin, which reduces BMP signaling. We show that BMPs act in a dose and time dependent manner in which early reduction of BMPs result in digit loss, while inhibiting overall BMP signaling between E10.5 and E11.5 allows polydactylous digit formation. During this period, inhibiting BMPs extends the duration of FGF signaling. Sox9 is initially expressed in normal digit ray domains but at reduced levels that correlate with the reduction in BMP signaling. The persistence of elevated FGF signaling likely promotes cell proliferation and survival, inhibiting the activation of Sox9 and secondarily, inhibiting the differentiation of Sox9-expressing chondrocytes. Our results provide new insights into the timing and clarify the mechanisms underlying BMP signaling during digit morphogenesis.

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Tbx2 Terminates Shh/Fgf Signaling in the Developing Mouse Limb Bud by Direct Repression of Gremlin1

Cited by 49 publications

References 58 publications

HAND2 Targets Define a Network of Transcriptional Regulators that Compartmentalize the Early Limb Bud Mesenchyme

HAND2 Targets Define a Network of Transcriptional Regulators that Compartmentalize the Early Limb Bud Mesenchyme

Diverse feather shape evolution enabled by coupling anisotropic signalling modules with self-organizing branching programme

Dynamics of BMP signaling in limb bud mesenchyme and polydactyly

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