Hoxa11 and Hoxd11 Regulate Chondrocyte Differentiation Upstream of Runx2 and Shox2 in Mice

Groß, Stefanie; Krause, Yvonne; Wuelling, Manuela; Vortkamp, Andrea

doi:10.1371/journal.pone.0043553

Cited by 43 publications

(43 citation statements)

References 50 publications

(66 reference statements)

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“…This sustained Hox expression in Shh −/− (Fig. 4I) could explain the favored elongation of skeletal elements, consistent with previous reports proposing that the elongation of skeletal elements requires the function of HoxA;D genes Gross et al, 2012;Zákány et al, 1997). In Shh −/− ;Gli3 −/− limb, proper elongation of skeletal elements is thus expected to be associated with HoxA;D function.…”

Section: Research Article Development 140 (10)supporting

confidence: 91%

“…Notably, we found that during the AER phase, reducing the HoxA;D gene dose in absence of Gli3 interferes with limb bud growth in a dose-dependent manner, both along the AP and PD axes. Previous studies suggesting that the elongation of skeletal elements requires HoxA;D function were based on ubiquitous gene inactivation Gross et al, 2012;Zákány et al, 1997). Our data suggest that at least part of the reported phenotype could have been due to defective growth during the AER phase.…”

Section: ;Gli3mentioning

confidence: 99%

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Decoupling the function of Hox and Shh in developing limb reveals multiple inputs of Hox genes on limb growth

et al. 2013

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SUMMARYLimb development relies on an exquisite coordination between growth and patterning, but the underlying mechanisms remain elusive. Anterior-posterior and proximal-distal specification initiates in early limb bud concomitantly with the proliferative expansion of limb cells. Previous studies have shown that limb bud growth initially relies on fibroblast growth factors (FGFs) produced in the apical ectodermal ridge (AER-FGFs), the maintenance of which relies on a positive-feedback loop involving sonic hedgehog (Shh) and the BMP antagonist gremlin 1 (Grem1). The positive cross-regulation between Shh and the HoxA and HoxD clustered genes identified an indirect effect of Hox genes on the maintenance of AER-FGFs but the respective function of Shh and Hox genes in this process remains unknown. Here, by uncoupling Hox and Shh function, we show that HoxA and HoxD genes are required for proper AER-FGFs expression, independently of their function in controlling Shh expression. In addition, we provide evidence that the Hoxdependent control of AER-FGF expression is achieved through the regulation of key mesenchymal signals, namely Grem1 and Fgf10, ensuring proper epithelial-mesenchymal interactions. Notably, HoxA and HoxD genes contribute to both the initial activation of Grem1 and the subsequent anterior expansion of its expression domain. We propose that the intricate interactions between Hox genes and the FGF and Shh signaling pathways act as a molecular network that ensures proper limb bud growth and patterning, probably contributing to the coordination of these two processes.

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Section: Research Article Development 140 (10)supporting

confidence: 91%

Section: ;Gli3mentioning

confidence: 99%

Decoupling the function of Hox and Shh in developing limb reveals multiple inputs of Hox genes on limb growth

et al. 2013

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“…This downregulation of Shox2 expression is transient, however, as HoxA c/c ; HoxD 2/2 animals show similar Shox2 expression at E11 to wild type, despite having a drastic difference in limb bud morphology ( Figure 5). A recent report demonstrated that Hox11 genes are required for Shox2 expression in the proliferating chondrocytes of the zeugopodal elements (Gross et al 2012), suggesting Hox genes could generally function upstream of Shox2 expression in these cells. To assess whether Hox genes are necessary for Shox2 activation in the developing humerus, ISH was performed on sections of wild-type and HoxA/D mutant limbs at E14.5.…”

Section: Resultsmentioning

confidence: 99%

“…Emerging evidence indicates that the activation of Runx2 is a critical point of regulation by these genes (Cobb et al 2006;VillavicencioLorini et al 2010;Gross et al 2012). The present work supports this general model and extends it by revealing that Shox2 and Hox genes genetically interact during the development of both the stylopod and zeugopod elements.…”

Section: Discussionmentioning

confidence: 99%

“…Runx2, which is expressed both by chondrocytes and the perichondrium, is essential for proper chondrocyte hypertrophy and the formation of osteoblasts, thus being important for both the proper development of the cartilage template and its eventual replacement by bone (Otto et al 1997;Yoshida et al 2004). As mutation of Shox2 or Hox genes results in a strong reduction or loss of Runx2 expression, a lack of chondrocyte maturation likely underlies regional shortening in these animals (Boulet and Capecchi 2004;Cobb et al 2006;Villavicencio-Lorini et al 2010;Gross et al 2012). The regulation of individual Hox and Shox genes follows precise spatial and temporal patterns of gene expression in the limb.…”

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confidence: 99%

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Genetic Interactions Between Shox2 and Hox Genes During the Regional Growth and Development of the Mouse Limb

2014

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The growth and development of the vertebrate limb relies on homeobox genes of the Hox and Shox families, with their independent mutation often giving dose-dependent effects. Here we investigate whether Shox2 and Hox genes function together during mouse limb development by modulating their relative dosage and examining the limb for nonadditive effects on growth. Using double mRNA fluorescence in situ hybridization (FISH) in single embryos, we first show that Shox2 and Hox genes have associated spatial expression dynamics, with Shox2 expression restricted to the proximal limb along with Hoxd9 and Hoxa11 expression, juxtaposing the distal expression of Hoxa13 and Hoxd13. By generating mice with all possible dosage combinations of mutant Shox2 alleles and HoxA/D cluster deletions, we then show that their coordinated proximal limb expression is critical to generate normally proportioned limb segments. These epistatic interactions tune limb length, where Shox2 underexpression enhances, and Shox2 overexpression suppresses, Hox-mutant phenotypes. Disruption of either Shox2 or Hox genes leads to a similar reduction in Runx2 expression in the developing humerus, suggesting their concerted action drives cartilage maturation during normal development. While we furthermore provide evidence that Hox gene function influences Shox2 expression, this regulation is limited in extent and is unlikely on its own to be a major explanation for their genetic interaction. Given the similar effect of human SHOX mutations on regional limb growth, Shox and Hox genes may generally function as genetic interaction partners during the growth and development of the proximal vertebrate limb.T HE vertebrate limb is a valuable model for studying the genetic coordination of a complex developing structure. The proximodistal axis of the limb is composed of discrete segments, the growth and development of which are selectively perturbed when individual, or combinations of, homeobox genes are disrupted. In mice, mutations of the paralogous Hox9 and Hox10 genes result in shortened stylopodal elements (containing the humerus and femur) (FromentalRamain et al. 1996a;Wellik and Capecchi 2003), deletions of Hox11 genes result in truncated zeugopodal elements (radius/ ulna and fibula/tibia) (Davis et al. 1995;Wellik and Capecchi 2003), and disruption of Hox13 genes results in agenesis of the autopod (metacarpals/metatarsals and the digits) (FromentalRamain et al. 1996b). Mutation of short stature homeobox (Shox) genes similarly gives rise to the disproportionate shortening of certain limb regions. In humans, loss of SHOX leads to the truncated zeugopod elements found in people with LeriWeill, Turner, and Langer syndromes (Rao et al. 1997;Belin et al. 1998;Shears et al. 1998;Zinn et al. 2002). While rodents have uniquely lost the Shox gene among mammals (Gianfrancesco et al. 2001), disruption of the widely conserved Shox2 gene results in severely shortened stylopodal elements in mice (Cobb et al. 2006). Thus, Hox and Shox gene perturbations each give ...

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Mammalian Embryo:HoxGenes

Nolte

Alexander

Krumlauf

2015

Encyclopedia of Life Sciences

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Hox genes are evolutionarily conserved transcription factors that play important roles in establishing the basic body plan of animals. Mammals have 39 Hox genes clustered into four chromosomal complexes. This gene family regulates the regional character and patterning of diverse structures along the anterior–posterior (A/P) axis of the embryo. Nested patterns of Hox gene expression generate a Hox combinatorial protein code that orchestrates the morphogenesis of structures in the nervous system, axial skeleton, limbs, intestine and many other tissues. In light of their key role in regulating morphogenesis across animal species, modulation of Hox expression or function over the course of evolution is believed to have been important in generating diversity. Key Concepts Axial patterning is the process that generates different regional characteristics during the development of a tissue, such as the nervous system or skeleton. Hox genes encode a family of transcription factors that regulate the identity of structures along the anterior–posterior (A/P) axis of embryos. Co‐linearity is the correlation between the order of Hox genes along a chromosome and their expression along the axis of an embryo. The collection of Hox proteins expressed in a region provides a combinatorial code for specifying diversity. Posterior prevalence is a model for explaining why some Hox proteins dominate over others when they are co‐expressed. Selector genes control the identity of a tissue. Homeotic transformation is the conversion of one structure into another due to loss or gain of selector gene activity. Segmentation subdivides a developing tissue, such as the hindbrain or skeleton, into repeating units that ultimately generate different structures along an axis. Subfunctionalisation is the partitioning of function and regulation between duplicated genes compared with the ancestral gene. Changes in Hox expression or function may be important for generating differences in structures during evolution of vertebrates. Cooption refers to the redeployment or coupling of a common molecular pathway to multiple patterning processes.

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Hoxa11 and Hoxd11 Regulate Chondrocyte Differentiation Upstream of Runx2 and Shox2 in Mice

Cited by 43 publications

References 50 publications

Decoupling the function of Hox and Shh in developing limb reveals multiple inputs of Hox genes on limb growth

Decoupling the function of Hox and Shh in developing limb reveals multiple inputs of Hox genes on limb growth

Genetic Interactions Between Shox2 and Hox Genes During the Regional Growth and Development of the Mouse Limb

Mammalian Embryo:HoxGenes

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