Expression of the short stature homeobox gene Shox is restricted by proximal and distal signals in chick limb buds and affects the length of skeletal elements

Tiecke, Eva; Bangs, Fiona; Blaschke, R.; Farrell, Elizabeth R.; Rappold, Gudrun; Tickle, Cheryll

doi:10.1016/j.ydbio.2006.07.008

Cited by 45 publications

(56 citation statements)

References 37 publications

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“…For example, Shox misexpression throughout the developing chick limb bud results in an ossification delay in the coracoid of the scapula and the ischium of the hip. Furthermore, similar to the expression pattern of Shox2 in the developing mouse stylopod, expression of Shox is downregulated in chondrogenic condensations of the chick zeugopod (Tiecke et al, 2006). And finally, Shox overexpression in chick limb bud micromass cultures results in significantly depressed expression of the chondrocyte maturation genes Ihh (Tiecke et al, 2006) and Fgfr3 (Decker et al, 2011).…”

Section: Discussionmentioning

confidence: 63%

Shox2regulates progression through chondrogenesis in the mouse proximal limb

Bobick

Cobb

2012

Journal of Cell Science

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SummaryIn humans, loss of SHOX gene function is responsible for the mesomelic short stature characteristic of Turner syndrome, Leri-Weill dyschondrosteosis, and Langer dysplasia. In a mouse model of SHOX deficiency, Prrx1-Cre-driven limb-specific deletion of the paralogous gene Shox2 results in severe rhizomelia. In this study, we show that Col2a1-Cre-driven deletion of Shox2 in developing chondrocytes also results in shortening of the stylopodial skeleton (i.e. humerus, femur) and that this rhizomelia is due to precocious chondrocyte maturation and hypertrophy. We demonstrate, using the micromass culture model system, that increased BMP activity triggers accelerated maturation and hypertrophy in Col2a1-Cre Shox2 mutant chondrocytes and we confirm in vivo that elevated transcript levels and expanded expression domains of Bmp2 and 4 are associated with premature formation of the hypertrophic zone in mutant humeri. In micromass cultures of Prrx1-Cre Shox2 mutant limb cells, we find that Shox2 deletion in undifferentiated mesenchymal cells results in increased BMP activity that enhances early chondrogenesis, but is insufficient to provoke chondrocyte maturation and hypertrophy. Similarly, shRNA-mediated Shox2 knockdown in multipotent C3H10T1/2 cells and primary mouse bone marrow mesenchymal stem cells results in spontaneous chondrogenesis in the absence of chondrostimulation, but again fails to induce progression through the later stages of chondrogenic differentiation. Importantly, exogenous BMP supplementation can overcome the block to maturation and hypertrophy caused by Shox2 depletion prior to overt chondrogenesis. Thus, we provide evidence that Shox2 regulates progression through chondrogenesis at two distinct stages -the onset of early differentiation and the transition to maturation and hypertrophy.

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Section: Discussionmentioning

confidence: 63%

Shox2regulates progression through chondrogenesis in the mouse proximal limb

Bobick

Cobb

2012

Journal of Cell Science

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“…It has indeed been previously shown that a human SHOX knock-in allele is able to compensate for the loss of mouse Shox2 in the developing forelimb (Liu et al 2011). Interestingly, the reported SHOX2 expression domains in chicks and humans are restricted to the stylopod (Clement-Jones et al 2000;Tiecke et al 2006), suggesting that the distally extended expression of mouse Shox2 may be a derived feature in rodents. And second, although the individual mutation of mouse Shox2 has little effect on the newborn zeugopod, its mutation in sensitized Hox backgrounds demonstrates its prominent function in this region.…”

Section: Discussionmentioning

confidence: 86%

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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Section: Box 2 Experimental Evidence For the Morphogen Gradient Modementioning

confidence: 99%

“…In chick wing buds, Shox is expressed in an intermediate region where it overlaps Meis expression proximally. This expression pattern could be explained by the fact that Shox is inhibited by distal FGF and by proximal RA signals (Tiecke et al, 2006).In summary, significant progress has been made in identifying the molecules involved in PD limb patterning but this has not clarified whether this process is best explained in terms of the progress zone or early specification model. In fact, in the next section we describe how the dissection of FGF genetics in the mouse limb has led to an alternative model that, again, has classical roots.…”

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confidence: 99%

Growing models of vertebrate limb development

2009

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The developing limb has been a very influential system for studying pattern formation in vertebrates. In the past, classical embryological models have explained how patterned structures are generated along the two principal axes of the limb: the proximodistal (shoulder to finger) and anteroposterior (thumb to little finger) axes. Over time, the genetic and molecular attributes of these patterning models have been discovered, while the role of growth in the patterning process has been only recently highlighted. In this review, we discuss these recent findings and propose how the various models of limb patterning can be reconciled. IntroductionThe developing limb has long been a pioneering model for understanding pattern formation: the process in which the spatial organisation of differentiated cells and tissues is generated in the embryo. One aspect of limb development that has perplexed several generations of researchers is the importance of growth. This might appear to be a trivial problem because growth occurs throughout the period when pattern is laid down and so, in the broadest sense, it is obviously required for development. However, controversy surrounds whether growth is required for the actual specification of pattern.Pattern formation can be considered as a two-step process; first cells are informed of their position and, thus, acquire a positional value (specification); cells then remember and interpret this value to form the appropriate structures (differentiation) (Wolpert, 1969). In the developing chick leg, specification cues can be experimentally overridden until quite a late stage, leading to altered differentiation and morphogenesis, thus revealing remarkable developmental plasticity (Dahn and Fallon, 2000). Three main scenarios for the role of growth in pattern formation have been suggested and can be illustrated by the classical French flag model (Wolpert, 1969;Wolpert, 1989). In one scenario, growth itself is proposed to specify positional values directly (Fig. 1A). In another, local growth generates positional values by intercalating existing disparate positional values, as seen in regenerating amphibian limbs (French et al., 1976) (Fig. 1B). In the third scenario, growth is proposed to play no direct patterning role, but simply to expand positional values that have already been specified by a different mechanism, such as a concentration gradient of a long-range morphogen (Fig. 1C).Studies of the genetic basis of some human congenital limb defects, such as Apert syndrome (Wilkie et al., 1995) and preaxial polydactyly (PPD) (Lettice et al., 2002) have complemented experimental findings in the main model organisms, the chick and the mouse. However, in order to understand the relationship between genotype and phenotype, we need to have a better grasp of the basic patterning mechanisms that operate during limb development, knowledge that could be incorporated into our current models of embryonic pattern formation. Thus, it is encouraging that several recent papers on limb development propose pa...

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Expression of the short stature homeobox gene Shox is restricted by proximal and distal signals in chick limb buds and affects the length of skeletal elements

Cited by 45 publications

References 37 publications

Shox2regulates progression through chondrogenesis in the mouse proximal limb

Shox2regulates progression through chondrogenesis in the mouse proximal limb

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

Growing models of vertebrate limb development

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