<i>Tbx6</i>controls left-right asymmetry through regulation of<i>Gdf1</i>

Concepcion, Daniel; Hamada, Hiroshi; Papaioannou, Virginia E.

doi:10.1242/bio.032565

Cited by 9 publications

(8 citation statements)

References 40 publications

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“…We observed consistent differential expression between biological replicates and identified 190 dysregulated genes by mRNA-seq (FDR <= 0.10) and ( GO analysis for Hh-dependent TFs identified somitogenesis and paraxial mesoderm, which share common genes for anterior mesoderm development during gastrulation, as the most highly represented terms ( Fig. 5A (59,74), is lost from all but the most distal mesoderm expression domains in Mesp1 Cre -Gli3R mutants (Fig. 5C).…”

Section: Transcriptional Profiling Identified Hh-dependent Transcriptsupporting

confidence: 53%

A Hedgehog-FGF signaling axis patterns anterior mesoderm during gastrulation

Guzzetta

Koska

Rowton

et al. 2019

Preprint

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The application of single cell technologies to early development holds promise for resolving complex developmental phenotypes. Here we define a novel role for Hedgehog (Hh) signaling for the formation of anterior mesoderm lineages during gastrulation. Single-cell transcriptome analysis of Hh-deficient mesoderm revealed selective deficits in anterior mesoderm populations that later translate to physical defects to anterior embryonic structures including the first pharyngeal arch, heart, and anterior somites. We found that Hh-dependent anterior mesoderm defects were cell non-autonomous to Hh-signal reception.Transcriptional profiling of Hh-deficient mesoderm during gastrulation revealed disruptions to both transcriptional patterning of the mesoderm and a key FGF signaling pathway for mesoderm migration. FGF4 protein application was able to restore cellular migration during gastrulation that was decreased by Hh pathway antagonism. These findings implicate that primitive streak-mediated regulation of anterior mesoderm patterning is controlled by a multicomponent signaling hierarchy activated by Hh signaling and executed by FGF signal transduction.

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Section: Transcriptional Profiling Identified Hh-dependent Transcriptsupporting

confidence: 53%

A Hedgehog-FGF signaling axis patterns anterior mesoderm during gastrulation

Guzzetta

Koska

Rowton

et al. 2019

Preprint

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“…In order to address such a connection during Xenopus LR development, we first analyzed the two myogenic marker genes tbx6 and myf5 in dmrt2 morphants. The genes were chosen as 1) tbx6 knockout mice display LRO defects and 2) murine myf5 is a direct transcriptional target of Dmrt2 ( Hadjantonakis et al, 2008 ; Sato et al, 2010 ; Concepcion et al, 2018 ). At neurula stages, both genes were expressed in presomitic mesoderm and importantly in sLRO cells ( Supplemental Figures S3A, B ), strongly suggesting a connection between myogenic pathways and sLRO morphogenesis.…”

Section: Resultsmentioning

confidence: 99%

“…We and others recently showed that Fgf signaling is crucial for sLRO and presomitic cells, suggesting a tight connection between sLRO morphogenesis and paraxial patterning/somitogenesis ( Sempou et al, 2018 ; Schneider et al, 2019 ). This notion is substantiated by the requirement of the t-box transcription factor Tbx6 for somitogenesis and LRO morphogenesis in mice ( Concepcion et al, 2018 ). In addition, Dmrt2, a transcription factor of the doublesex and mab3-related family, is crucial for somite development, and its loss-of-function results in LR defects in fish embryos ( Meng et al, 1999 ; Saúde et al, 2005 ; Liu et al, 2009 ).…”

Section: Introductionmentioning

confidence: 92%

dmrt2 and myf5 Link Early Somitogenesis to Left-Right Axis Determination in Xenopus laevis

Tingler

Brugger

Feistel

et al. 2022

Front. Cell Dev. Biol.

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The vertebrate left-right axis is specified during neurulation by events occurring in a transient ciliated epithelium termed left-right organizer (LRO), which is made up of two distinct cell types. In the axial midline, central LRO (cLRO) cells project motile monocilia and generate a leftward fluid flow, which represents the mechanism of symmetry breakage. This directional fluid flow is perceived by laterally positioned sensory LRO (sLRO) cells, which harbor non-motile cilia. In sLRO cells on the left side, flow-induced signaling triggers post-transcriptional repression of the multi-pathway antagonist dand5. Subsequently, the co-expressed Tgf-β growth factor Nodal1 is released from Dand5-mediated repression to induce left-sided gene expression. Interestingly, Xenopus sLRO cells have somitic fate, suggesting a connection between LR determination and somitogenesis. Here, we show that doublesex and mab3-related transcription factor 2 (Dmrt2), known to be involved in vertebrate somitogenesis, is required for LRO ciliogenesis and sLRO specification. In dmrt2 morphants, misexpression of the myogenic transcription factors tbx6 and myf5 at early gastrula stages preceded the misspecification of sLRO cells at neurula stages. myf5 morphant tadpoles also showed LR defects due to a failure of sLRO development. The gain of myf5 function reintroduced sLRO cells in dmrt2 morphants, demonstrating that paraxial patterning and somitogenesis are functionally linked to LR axis formation in Xenopus.

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“…Gdf1 has been previously shown to act as a co‐ligand which potentiates Nodal signal (Sempou & Khokha, ; Tanaka, Sakuma, Nakamura, Hamada, & Saijoh, ). Furthermore, variants in TBX6 , recently implicated in laterality defects, have been demonstrated to do so via downregulation of Gdf1 expression (Concepcion, Hamada, & Papaioannou, ).…”

Section: Discussionmentioning

confidence: 99%

A founder truncating variant in GDF1 causes autosomal‐recessive right isomerism and associated congenital heart defects in multiplex Arab kindreds

Marek‐Yagel

Bolkier

Barel

et al. 2020

American J of Med Genetics Pt A

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The genetic basis of congenital heart malformations associated with disruption of left-right (L-R) asymmetry is broad and heterogenous, with variants in over 25 genes implicated thus far. Of these, deleterious variants in the Growth/Differentiation Factor 1 (GDF1) gene have been shown to cause heterotaxy with varied complex heart malformations of left-right patterning, in 23 individuals reported to date, either in monoallelic or biallelic state. We report three unrelated individuals exhibiting right isomerism with congenital heart defects, each originating from a consanguineous kindred of Arab-Muslim descent. Using whole exome sequencing, a shared novel homozygous truncating c.608G > A (p.W203*) variant in the GDF1 gene was revealed as the molecular basis of their disease. Subsequently, targeted sequencing of this variant showed full segregation with the disease in these families, with a total of over 15 reportedly affected individuals, enabling genetic counseling, prenatal diagnosis, and planning of future pregnancies. Our findings further confirm the association of

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Tbx6controls left-right asymmetry through regulation ofGdf1

Cited by 9 publications

References 40 publications

A Hedgehog-FGF signaling axis patterns anterior mesoderm during gastrulation

A Hedgehog-FGF signaling axis patterns anterior mesoderm during gastrulation

dmrt2 and myf5 Link Early Somitogenesis to Left-Right Axis Determination in Xenopus laevis

A founder truncating variant in GDF1 causes autosomal‐recessive right isomerism and associated congenital heart defects in multiplex Arab kindreds

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