Regulation of Zebrafish Skeletogenesis by ext2/dackel and papst1/pinscher

Clément, Aurélie; Wiweger, Małgorzata; Hardt, Sophia von der; Rusch, Melissa; Selleck, Scott B.; Chien, Chi Bin; Roehl, Henry

doi:10.1371/journal.pgen.1000136

Cited by 120 publications

(134 citation statements)

References 50 publications

(67 reference statements)

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“…The expression around the endoskeletal radials is consistent with published data (Crotwell et al, 2001). Antisense RNA probes were prepared using the following templates: gdf5 (Clement et al, 2008); evx1 (Thaeron et al, 2000).…”

Section: In Situ Hybridizationsupporting

confidence: 71%

Evx1 is required for joint formation in zebrafish fin dermoskeleton

Schulte

Allen

England

et al. 2011

Developmental Dynamics

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The transcription factor Evx1 is expressed in the joints between individual lepidotrichia (bony ray) segments and at the distal tips of the lepidotrichia in developing zebrafish fins. It is also expressed in the apical growth zone in regenerating fins. However, so far there is no functional evidence that addresses whether Evx1 is required for any aspect of fin development or regeneration. In this study, we use a novel mutation in evx1 to address this. We find that Evx1 is not required for either fin outgrowth or regeneration. All of the fins form normally in evx1 mutants, and there are no significant changes in fin length. In contrast, Evx1 is required for lepidotrichia joint formation during both fin development and regeneration. This is a very specific phenotype as both lepidotrichia hemisegment separations and lepidotrichia bifurcations still form normally in evx1 mutant fins, as do joints in the more proximal endoskeletal radials. Developmental Dynamics 240:1240-1248,

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Section: In Situ Hybridizationsupporting

confidence: 71%

Evx1 is required for joint formation in zebrafish fin dermoskeleton

Schulte

Allen

England

et al. 2011

Developmental Dynamics

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“…Osteochondromas originate either from the chondrocytes of the growth plate or the cells of the perichondrium due to homozygous inactivation of EXT1 or EXT2 (Cle´ment et al, 2008;Jones et al, 2010;Matsumoto et al, 2010). During osteochondromagenesis, wild-type chondrocytes and cells with homozygous inactivation of EXT are shown to intermingle in the cartilaginous cap (de Andrea et al, , 2011Jones et al, 2010;Matsumoto et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…In sporadic osteochondromas, homozygous deletions of EXT1 are identified (Hameetman et al, 2007b;Reijnders et al, 2010;Zuntini et al, 2010;Szuhai et al, 2011). Recent experimental studies using mice and zebrafish knockdown models show that homozygous inactivation of Ext1 or Ext2 is required for osteochondromagenesis (Cle´ment et al, 2008;Jones et al, 2010;Matsumoto et al, 2010). In humans, loss of the remaining wild-type allele of EXT has been detected in approximately 40% of sporadic and multiple osteochondromas (Hameetman et al, 2007b;Reijnders et al, 2010;Zuntini et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

et al. 2011

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Secondary peripheral chondrosarcoma is the result of malignant transformation of a pre-existing osteochondroma, the most common benign bone tumor. Osteochondromas are caused by genetic abnormalities in EXT1 or EXT2: homozygous deletion of EXT1 characterizes sporadic osteochondromas (non-familial/solitary), and germline mutations in EXT1 or EXT2 combined with loss of heterozygosity define hereditary multiple osteochondromas. While cells with homozygous inactivation of EXT and wild-type cells shape osteochondromas, the cellular composition of secondary peripheral chondrosarcomas and the role of EXT in their formation have remained unclear. We report using a targeted-tiling-resolution oligo-array-CGH (array comparative genomic hybridization) that homozygous deletions of EXT1 or EXT2 are much less frequently detected (2/17, 12%) in sporadic secondary peripheral chondrosarcomas than expected based on the assumption that they originate in sporadic osteochondromas, in which homozygous inactivation of EXT1 is found in B80% of our cases. FISH with an EXT1 probe confirmed that, unlike sporadic osteochondromas, cells from sporadic secondary peripheral chondrosarcomas predominantly retained one (hemizygous deleted loci) or both copies (wild-type) of the EXT1 locus. By immunohistochemistry, we confirm the presence of cells with dysfunctional EXT1 in sporadic osteochondromas and show cells with functional EXT1 in sporadic secondary peripheral chondrosarcomas. These immuno results were verified in osteochondromas and secondary peripheral chondrosarcomas in the setting of hereditary multiple osteochondromas. Our data therefore point to a model of oncogenesis in which the osteochondroma creates a niche in which wild-type cells with functional EXT are predisposed to acquire other mutations giving rise to secondary peripheral chondrosarcoma, indicating that EXT-independent mechanisms are involved in the pathogenesis of secondary peripheral chondrosarcoma.

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“…Zebrafish dackel (dak/ext2 ) mutant has cartilage defects that strongly resemble those seen in patients with multiple osteochondromas [59]. Interestingly, dak chondrocytes (chondrocytes with homozygous mutation in ext2 ) behave as wild-type cells when juxtaposed with heparan sulphatesecreting cells and form osteochondroma-like outgrowths when implanted at the edge of wild-type cartilage [60]. This shows that the secretion of heparan sulphate from the neighbouring wild-type chondrocytes is able to rescue the chondrocytes with homozygous mutation in ext2.…”

Section: A Propitious Micro-environment For Osteochondromagenesismentioning

confidence: 99%

“…This shows that the secretion of heparan sulphate from the neighbouring wild-type chondrocytes is able to rescue the chondrocytes with homozygous mutation in ext2. Only, at the edge of the cartilage elements, where the level of heparan sulphate is decreased, chondrocytes with homozygous mutation in ext2 are able to form outgrowths [60].…”

Section: A Propitious Micro-environment For Osteochondromagenesismentioning

confidence: 99%

Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

Andrea¹,

Hogendoorn²

2011

The Journal of Pathology

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Chondrocytes interact with their neighbours through their cartilaginous extracellular matrix (ECM).Chondrocyte-matrix interactions compensate the lack of cell-cell contact and are modulated by proteoglycans and other molecules. The epiphyseal growth plate is a highly organized tissue responsible for long bone elongation. The growth plate is regulated by gradients of morphogens that are established by proteoglycans. Morphogens diffuse across the ECM, creating short-and long-range signalling that lead to the formation of a polarized tissue. Mutations affecting genes that modulate cell-matrix interactions are linked to several human disorders. Homozygous mutations of EXT1/EXT2 result in reduced synthesis and shortened heparan sulphate chains on both cell surface and matrix proteoglycans. This disrupts the diffusion gradients of morphogens and signal transduction in the epiphyseal growth plate, contributing to loss of cell polarity and osteochondroma formation. Osteochondromas are cartilage-capped bony projections arising from the metaphyses of endochondral bones adjacent to the growth plate. The osteochondroma cap is formed by cells with homozygous mutation of EXT1/EXT2 and committed stem cells/wild-type chondrocytes. Osteochondroma serves as a niche (a permissive environment), which facilitates the committed stem cells/wild-type chondrocytes to acquire secondary genetic changes to form a secondary peripheral chondrosarcoma. In such a scenario, the micro-environment is the site of the initiating processes that ultimately lead to cancer.

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Regulation of Zebrafish Skeletogenesis by ext2/dackel and papst1/pinscher

Cited by 120 publications

References 50 publications

Evx1 is required for joint formation in zebrafish fin dermoskeleton

Evx1 is required for joint formation in zebrafish fin dermoskeleton

Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

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