The synpolydactyly homolog (spdh) mutation in the mouse – a defect in patterning and growth of limb cartilage elements

Albrecht, Andrea N.; Schwabe, Georg C.; Stricker, Sigmar; Böddrich, Annett; Wanker, Erich E.; Mundlos, Stefan

doi:10.1016/s0925-4773(01)00639-6

Cited by 42 publications

(41 citation statements)

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“…RA is known to play a role in the sequential activation of Hox genes in limb development by promoting anterior Hox genes and delaying posterior ones (51). The expression of Hox genes has been extensively studied in Spdh mice (25,52). No differences were identified, indicating that the level of RA dysregulation in Spdh mice is not sufficient to induce misexpression.…”

Section: Discussionmentioning

confidence: 99%

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Mutant Hoxd13 induces extra digits in a mouse model of synpolydactyly directly and by decreasing retinoic acid synthesis

et al. 2008

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Individuals with the birth defect synpolydactyly (SPD) have 1 or more digit duplicated and 2 or more digits fused together. One form of SPD is caused by polyalanine expansions in homeobox d13 (Hoxd13). Here we have used the naturally occurring mouse mutant that has the same mutation, the SPD homolog (Spdh) allele, and a similar phenotype, to investigate the molecular pathogenesis of SPD. A transgenic approach and crossing experiments showed that the Spdh allele is a combination of loss and gain of function. Here we identify retinaldehyde dehydrogenase 2 (Raldh2), the rate-limiting enzyme for retinoic acid (RA) synthesis in the limb, as a direct Hoxd13 target and show decreased RA production in limbs from Spdh/Spdh mice. Intrauterine treatment with RA restored pentadactyly in Spdh/Spdh mice. We further show that RA and WT Hoxd13 suppress chondrogenesis in mesenchymal progenitor cells, whereas Hoxd13 encoded by Spdh promotes cartilage formation in primary cells isolated from Spdh/Spdh limbs, and that this was associated with increased expression of Sox6/9. Increased Sox9 expression and ectopic cartilage formation in the interdigital mesenchyme of limbs from Spdh/Spdh mice suggest uncontrolled differentiation of these cells into the chondrocytic lineage. Thus, we propose that mutated Hoxd13 causes polydactyly in SPD by inducing extraneous interdigital chondrogenesis, both directly and indirectly, via a reduction in RA levels.

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Section: Discussionmentioning

confidence: 99%

“…Timed matings were produced, and 12 pm on the day of vaginal plug was considered E0.5. DNA from tail tip, amnion, or liver was used for genotyping, which was performed as described previously (52).…”

Section: Methodsmentioning

confidence: 99%

Mutant Hoxd13 induces extra digits in a mouse model of synpolydactyly directly and by decreasing retinoic acid synthesis

et al. 2008

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“…Whole-mount hybridizaton was performed as described (Albrecht et al, 2002). Photography was with a binocular microscope and camera (Leica, Bensheim, Germany).…”

Section: In Situ Hybridizationmentioning

confidence: 99%

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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“…Whole-mount in situ hybridization was performed as described previously (Albrecht et al, 2002) by using embryos of stages E10.5 obtained by timed matings from the Ror2 k.o. cross.…”

Section: In Situ Hybridizationmentioning

confidence: 99%

Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome

Schwabe

Trepczik

Süring

et al. 2004

Developmental Dynamics

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Robinow syndrome (RS) is a human dwarfism syndrome characterized by mesomelic limb shortening, vertebral and craniofacial malformations and small external genitals. We have analyzed Ror2 -/-mice as a model for the developmental pathology of RS. Our results demonstrate that vertebral malformations in Ror2 -/-mice are due to reductions in the presomitic mesoderm and defects in somitogenesis. Mesomelic limb shortening in Ror2 -/-mice is a consequence of perturbed chondrocyte differentiation. Moreover, we show that the craniofacial phenotype is caused by a midline outgrowth defect. Ror2 expression in the genital tubercle and its reduced size in Ror2 -/-mice makes it likely that Ror2 is involved in genital development. In conclusion, our findings suggest that Ror2 is essential at multiple sites during development. The Ror2 -/-mouse provides a suitable model that may help to explain many of the underlying developmental malformations in individuals with Robinow syndrome. Developmental Dynamics 229: 400 -410, 2004.

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The synpolydactyly homolog (spdh) mutation in the mouse – a defect in patterning and growth of limb cartilage elements

Cited by 42 publications

References 42 publications

Mutant Hoxd13 induces extra digits in a mouse model of synpolydactyly directly and by decreasing retinoic acid synthesis

Mutant Hoxd13 induces extra digits in a mouse model of synpolydactyly directly and by decreasing retinoic acid synthesis

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

Ror2 knockout mouse as a model for the developmental pathology of autosomal recessive Robinow syndrome

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