Cloning and expression pattern of chicken <i>Ror2</i> and functional characterization of truncating mutations in Brachydactyly type B and Robinow syndrome

Stricker, Sigmar; Wijk, Nicole Verhey van; Witte, Florian; Brieske, Norbert; Seidel, Kathrin; Mundlos, Stefan

doi:10.1002/dvdy.20993

Cited by 37 publications

(27 citation statements)

References 36 publications

(48 reference statements)

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“…However, this is not accompanied by changes in the number or density of BrdU-labeled cells in the cartilage (E12.5, E18.5) or in the growth plates (P5). This is in agreement with observations in Ror2 -/-mice (Schwabe et al, 2004), or after the overexpression of dominant-negative forms of Ror2 in chicken (Stricker et al, 2006). Growth of the cartilaginous anlagen is a complex process that results from cellular recruitment from the mesenchyme underlying the perichondrium, as well as from chondrocyte proliferation in the hyaline cartilage and, especially, in the growth plates of the long bones, once they are formed (Dodds, 1930).…”

Section: Research Articlesupporting

confidence: 91%

The mutationROR2W749X, linked to human BDB, is a recessive mutation in the mouse, causing brachydactyly, mediating patterning of joints and modeling recessive Robinow syndrome

et al. 2008

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Mutations in ROR2 result in a spectrum of genetic disorders in humans that are classified, depending on the nature of the mutation and the clinical phenotype, as either autosomal dominant brachydactyly type B (BDB, MIM 113000) or recessive Robinow syndrome (RRS, MIM 268310). In an attempt to model BDB in mice, the mutation W749X was engineered into the mouse Ror2 gene. In contrast to the human situation, mice heterozygous for Ror2 W749FLAG are normal and do not develop brachydactyly, whereas homozygous mice exhibit features resembling RRS. Furthermore, both Ror2 W749FLAG/W749FLAG and a previously engineered mutant, Ror2 TMlacZ/TMlacZ , lack the P2/P3 joint. Absence of Gdf5 expression at the corresponding interzone suggests that the defect is in specification of the joint. As this phenotype is absent in mice lacking the entire Ror2 gene, it appears that specification of the P2/P3 joint is affected by ROR2 activity. Finally, Ror2 W749FLAG/W749FLAG mice survive to adulthood and exhibit phenotypes (altered body composition, reduced male fertility) not observed in Ror2 knockout mice, presumably due to the perinatal lethality of the latter. Therefore, Ror2 W749FLAG/W749FLAG mice represent a postnatal model for RRS, provide insight into the mechanism of joint specification, and uncover novel roles of Ror2 in the mouse.

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Section: Research Articlesupporting

confidence: 91%

The mutationROR2W749X, linked to human BDB, is a recessive mutation in the mouse, causing brachydactyly, mediating patterning of joints and modeling recessive Robinow syndrome

et al. 2008

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“…In Situ mRNA Hybridization-In situ hybridization for Adamts16 mRNA was performed according to the protocol of Stricker et al (32). Briefly, tissues were cryosectioned and fixed in freshly prepared paraformaldehyde (4% in PBS).…”

Section: Methodsmentioning

confidence: 99%

Transcriptional Regulation by the Wilms Tumor Protein, Wt1, Suggests a Role of the Metalloproteinase Adamts16 in Murine Genitourinary Development

Jacobi¹,

Rudigier

Scholz

et al. 2013

Journal of Biological Chemistry

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Background: ADAMTS16 is a mammalian metalloproteinase with unknown function. Results: Transcription of the Adamts16 gene is regulated by Wilms tumor protein Wt1, and knockdown of Adamts16 reduces branching morphogenesis in cultured embryonic kidneys. Conclusion: Adamts16 is a Wt1 target gene during murine genitourinary development. Significance: The findings provide novel insights into gene regulatory networks controlling kidney and gonad development.

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“…ISHs on whole-mount embryos as well as on paraffin sections were performed as previously described (30).…”

Section: Methodsmentioning

confidence: 99%

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region

Witte

Chan

Economides

et al. 2010

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

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Elongation of the digit rays resulting in the formation of a defined number of phalanges is a process poorly understood in mammals, whereas in the chicken distal mesenchymal bone morphogenetic protein (BMP) signaling in the so-called phalanx-forming region (PFR) or digit crescent (DC) seems to be involved. The human brachydactylies (BDs) are inheritable conditions characterized by variable degrees of digit shortening, thus providing an ideal model to analyze the development and elongation of phalanges. We used a mouse model for BDB1 (Ror2 W749X/W749X ) lacking middle phalanges and show that a signaling center corresponding to the chick PFR exists in the mouse, which is diminished in BDB1 mice. This resulted in a strongly impaired elongation of the digit condensations due to reduced chondrogenic commitment of undifferentiated distal mesenchymal cells. We further show that a similar BMP-based mechanism accounts for digit shortening in a mouse model for the closely related condition BDA1 (Ihh E95K/E95K ), altogether indicating the functional significance of the PFR in mammals. Genetic interaction experiments as well as pathway analysis in BDB1 mice suggest that Indian hedgehog and WNT/β-catenin signaling, which we show is inhibited by receptor tyrosine kinase-like orphan receptor 2 (ROR2) in distal limb mesenchyme, are acting upstream of BMP signaling in the PFR. T he appendicular skeleton arises as a continuous cartilaginous condensation in the center of the limb bud that develops in a proximal to distal sequence. Distal outgrowth is under the control of fibroblast growth factor (FGF) signaling from the apical ectodermal ridge (AER), which accounts for proliferation in the subridge mesenchyme and prevents premature differentiation of mesenchymal cells, thus maintaining a progenitor pool. Cells leaving the range of AER-FGF signaling undergo differentiation into the mesenchymal cell lineages of the limb bud (1, 2).Evidence from the chick indicates that bone morphogenetic protein (BMP)/pSMAD1/5/8 signaling in a population of cells in front of the growing condensation, referred to as the phalanxforming region (PFR) or digit crescent (3, 4), is involved in the elongation of the digital rays. This work suggests that the PFR acts as a signaling center to drive distal elongation of the digit and thus determines the number of phalanges via commitment of distal mesenchymal cells to the cartilage condensation. However, evidence for such a mechanism in the mouse or human is missing.If a PFR-like structure exists in mammals, its failure is expected to cause digit malformation phenotypes such as digit shortening and loss of phalanges. This phenotypic spectrum is typical for a family of human inheritable malformations, the brachydactylies (BDs), which are characterized by the absence or reduction of individual phalanges and/or metacarpals (5). Intriguingly, several mutations causing human BDs (BDA2, BDB2, and BDC) affect the BMP pathway (5), which suggests the involvement of a PFRlike structure in digit growth.BD types A1 and B1...

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Cloning and expression pattern of chicken Ror2 and functional characterization of truncating mutations in Brachydactyly type B and Robinow syndrome

Cited by 37 publications

References 36 publications

The mutationROR2W749X, linked to human BDB, is a recessive mutation in the mouse, causing brachydactyly, mediating patterning of joints and modeling recessive Robinow syndrome

The mutationROR2W749X, linked to human BDB, is a recessive mutation in the mouse, causing brachydactyly, mediating patterning of joints and modeling recessive Robinow syndrome

Transcriptional Regulation by the Wilms Tumor Protein, Wt1, Suggests a Role of the Metalloproteinase Adamts16 in Murine Genitourinary Development

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region

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