Growth differentiation factor 11 signaling controls retinoic acid activity for axial vertebral development

Lee, Young Jae; McPherron, Alexandra C.; Choe, Susan; Sakai, Yasuo; Chandraratna, Roshantha A.S.; Lee, Se Jin; Oh, S. Paul

doi:10.1016/j.ydbio.2010.08.022

Cited by 37 publications

(32 citation statements)

References 45 publications

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“…LTBP2 was found to inhibit the extracellular processing of proGdf11 to regulate the activity of growth differentiation factor (Gdf11), which is a member of the TGFβ superfamily (Sun et al 2011). Gdf11 −/− mice were reported to exhibit anterior transformations of the axial skeleton, resulting in an increase in the number of ribs from 13 (wild type) to 18 (McPherron et al 1999;Lee et al 2010). The full-length porcine LTBP2 mRNA sequence is not available in the GenBank database.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide study refines the quantitative trait locus for number of ribs in a Large White × Minzhu intercross pig population and reveals a new candidate gene

Zhang

Yue

et al. 2016

Mol Genet Genomics

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In China, sparerib is one of the most valuable parts of the pork carcass. As a result, candidate gene mining for number of ribs has become an interesting study focus. To examine the genetic basis for this major trait, we genotyped 596 individuals from an F2 Large White × Minzhu intercross pig population using the PorcineSNP60 Genotyping BeadChip. The genome-wide association study identified a locus for number of ribs in a 2.38-Mb region on Sus scrofa chromosome 7 (SSC7 of Sus scrofa genome assembly, Sscrofa10.2). We identified the top significant SNP ASGA0035536, which explained 16.51 % of the phenotypic variance. A previously reported candidate causal mutation (g.19034 A>C) in vertebrae development-associated gene VRTN explained 8.79 % of the phenotypic variation on number of ribs and had a much lower effect than ASGA0035536. Haplotype sharing analysis in F1 boars localized the rib number QTL to a 951-kb interval on SSC7. This interval encompassed 17 annotated genes in Sscrofa10.2, including the previously reported VRTN candidate gene. Of the 17 candidate genes, LTBP2, which encodes a latent transforming growth factor beta binding protein, was previously reported to indirectly regulate the activity of growth differentiation factor Gdf11, which has been shown to increase the number of ribs in knock-out mice. Thus, we propose LTBP2 as a good new candidate gene for number of ribs in the pig population. This finding advances our understanding of the genetic architecture of rib number in pigs.

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Section: Discussionmentioning

confidence: 99%

Genome-wide study refines the quantitative trait locus for number of ribs in a Large White × Minzhu intercross pig population and reveals a new candidate gene

Zhang

Yue

et al. 2016

Mol Genet Genomics

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“…A similar coordinated temporal shift in the trunk-to-tail Hox code has been demonstrated in Gdf11 −/− mice (56), which show conservation in the types of vertebral transformations we observe here in miR-196 mutant embryos. In this context, Gdf11 appears to work via retinoic acid signaling (57,65), and whether altered Gdf11 and retinoic acid signaling contribute to miR-196 phenotypic alterations remains to be tested. miR-196 Activity Constrains Total Vertebral Number.…”

Section: Discussionmentioning

confidence: 99%

Independent regulation of vertebral number and vertebral identity by microRNA-196 paralogs

Wong

Agarwal

Mansfield

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The Hox genes play a central role in patterning the embryonic anterior-to-posterior axis. An important function of Hox activity in vertebrates is the specification of different vertebral morphologies, with an additional role in axis elongation emerging. The miR-196 family of microRNAs (miRNAs) are predicted to extensively target Hox 3′ UTRs, although the full extent to which miR-196 regulates Hox expression dynamics and influences mammalian development remains to be elucidated. Here we used an extensive allelic series of mouse knockouts to show that the miR-196 family of miRNAs is essential both for properly patterning vertebral identity at different axial levels and for modulating the total number of vertebrae. All three miR-196 paralogs, 196a1, 196a2, and 196b, act redundantly to pattern the midthoracic region, whereas 196a2 and 196b have an additive role in controlling the number of rib-bearing vertebra and positioning of the sacrum. Independent of this, 196a1, 196a2, and 196b act redundantly to constrain total vertebral number. Loss of miR-196 leads to a collective up-regulation of numerous trunk Hox target genes with a concomitant delay in activation of caudal Hox genes, which are proposed to signal the end of axis extension. Additionally, we identified altered molecular signatures associated with the Wnt, Fgf, and Notch/segmentation pathways and demonstrate that miR-196 has the potential to regulate Wnt activity by multiple mechanisms. By feeding into, and thereby integrating, multiple genetic networks controlling vertebral number and identity, miR-196 is a critical player defining axial formulae.

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“…In addition, some mutations of the Bmp signaling pathway also affect vertebral patterning and identity (Ikeya et al, 2006;Katagiri et al, 1998;McMahon et al, 1998;McPherron et al, 1999;Miura et al, 2006;Oh and Li, 1997). In particular, mutations of Gdf11 or ActRIIB lead to homeotic transformations throughout the axial skeleton (Lee et al, 2010;McPherron et al, 1999;Oh and Li, 1997;Oh et al, 2002). Hox gene expression patterns are believed to form a ''Hox code'' essential for normal vertebral patterning (Alexander et al, 2009;Iimura et al, 2009;Iimura and Pourquie, 2007;Krumlauf, 1994;Mallo et al, 2010;Tschopp and Duboule, 2011;Wellik, 2007;Young and Deschamps, 2009).…”

Section: Introductionmentioning

confidence: 99%

Ndrg2 regulates vertebral specification in differentiating somites

Huang

Zhao

Zhou

et al. 2012

Developmental Biology

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It is generally thought that vertebral patterning and identity are globally determined prior to somite formation. Relatively little is known about the regulators of vertebral specification after somite segmentation. Here, we demonstrated that Ndrg2, a tumor suppressor gene, was dynamically expressed in the presomitic mesoderm (PSM) and at early stage of differentiating somites. Loss of Ndrg2 in mice resulted in vertebral homeotic transformations in thoracic/lumbar and lumbar/sacral transitional regions in a dose-dependent manner. Interestingly, the inactivation of Ndrg2 in osteoblasts or chondrocytes caused defects resembling those observed in Ndrg2(-/-) mice, with a lower penetrance. In addition, forced overexpression of Ndrg2 in osteoblasts or chondrocytes also conferred vertebral defects, which were distinct from those in Ndrg2(-/-) mice. These genetic analyses revealed that Ndrg2 modulates vertebral identity in segmented somites rather than in the PSM. At the molecular level, combinatory alterations of the amount of Hoxc8-11 gene transcripts were detected in the differentiating somites of Ndrg2(-/-) embryos, which may partially account for the vertebral defects in Ndrg2 mutants. Nevertheless, Bmp/Smad signaling activity was elevated in the differentiating somites of Ndrg2(-/-) embryos. Collectively, our findings unveiled Ndrg2 as a novel regulator of vertebral specification in differentiating somites.

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Growth differentiation factor 11 signaling controls retinoic acid activity for axial vertebral development

Cited by 37 publications

References 45 publications

Genome-wide study refines the quantitative trait locus for number of ribs in a Large White × Minzhu intercross pig population and reveals a new candidate gene

Genome-wide study refines the quantitative trait locus for number of ribs in a Large White × Minzhu intercross pig population and reveals a new candidate gene

Independent regulation of vertebral number and vertebral identity by microRNA-196 paralogs

Ndrg2 regulates vertebral specification in differentiating somites

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