Brachydactyly

Indian Hedgehog (Ihh) regulates chondrocyte and osteoblast differentiation through the Glioma-associated oncogene homolog (Gli) transcription factors. Previous in vitro studies suggested that Speckletype POZ protein (Spop), part of the Cullin-3 (Cul3) ubiquitin ligase complex, targets Gli2 and Gli3 for degradation and negatively regulates Hedgehog (Hh) signaling. In this study, we found defects in chondrocyte and osteoblast differentiation in Spop-null mutant mice. Strikingly, both the full-length and repressor forms of Gli3, but not Gli2, were up-regulated in Spop mutants, and Ihh target genes Patched 1 (Ptch1) and parathyroid hormone-like peptide (Pthlh) were down-regulated, indicating compromised Hh signaling. Consistent with this finding, reducing Gli3 dosage greatly rescued the Spop mutant skeletal defects. We further show that Spop directly targets the Gli3 repressor for ubiquitination and degradation. Finally, we demonstrate in a conditional mutant that loss of Spop results in brachydactyly and osteopenia, which can be rescued by reducing the dosage of Gli3. In summary, Spop is an important positive regulator of Ihh signaling and skeletal development.T he human skeleton provides essential mechanical support, mobility, and mineral storage critical for health (1). In development, most bones form through endochondral ossification in which chondrocytes in the growth plate proliferate, undergo hypertrophic differentiation, and secrete calcium-containing extracellular matrix (2). The osteoblasts in the perichondrium, a thin layer of tissue surrounding the cartilage, replace the dying chondrocytes and secrete more bone matrix. On the other hand, osteoclasts, derived from white blood cells, invade and digest bone matrix. The balance between the osteoblast and osteoclast activities allows calcium homeostatic control and bone health. In osteopenia and osteoporosis, conditions afflicting more than 10 million Americans, an abnormal decrease in osteoblast activity or increase in osteoclast activity results in the loss of bone mass (1, 3). Unfortunately, our understanding of these bone diseases has been hindered by incomplete knowledge in the molecular mechanisms underlying endochondral bone development and remodeling.Indian Hedgehog (Ihh), a member of the Hedgehog (Hh) family of signaling proteins, is essential for endochondral bone development (4). Ihh regulates gene expression through the Gli family of transcription factors, which act as both transcriptional activators and repressors (5). In the absence of Hh, efficient proteolytic processing turns Gli3 into a transcriptional repressor (Gli3R) whereas processing of Gli2 is rather inefficient (6-8). Hh inhibits Gli processing and converts the full-length Gli proteins into transcriptional activators. Both Gli2 and Gli3 play important roles in the regulation of bone formation downstream of Ihh (9-12).Ihh maintains the expression of parathyroid hormone-like peptide (Pthlh) (Mouse Genome Informatics) in the periarticular perichondrium (13), which then stimulates the prol...

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“…Therefore, Spop cKO can serve as a model for brachydactyly, a common but poorly understood congenital anomaly (27).…”

Section: Defective Chondrocyte Hypertrophy Results In Brachydactyly Imentioning

confidence: 99%

Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

Cai

Liu

2016

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

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“…Another class of brachydactyly (BDA2) results from either mutation of gdf5 (Ploger et al 2008), dominant negative mutation of the receptor BmpR1B (Lehmann et al 2003) or duplication of a conserved regulatory element in the Bmp2 gene (Dathe et al 2009). In fact, all documented examples of isolated brachydactyly can be linked directly or indirectly to altered BMP signal transduction (Temtamy & Aglan, 2008).…”

Section: Ectopic Limb Formation Can Results From Noggin Over-expressionmentioning

confidence: 99%

“…Brachydactyly phenotypes result from late-stage inactivation of BMP signaling in the autopod Brachydactyly, or shortening of the digits, can arise from failed growth of the autopod elements or from failed development of the distal elements (Temtamy & Aglan, 2008). When tadpoles were induced to overexpress Noggin in late limb development, the predominant phenotype was brachydactyly arising from failure to form the correct number of phalanges, with metacarpals and tarsals less affected.…”

Section: Ectopic Limb Formation Can Results From Noggin Over-expressionmentioning

confidence: 99%

Attenuation of bone morphogenetic protein signaling during amphibian limb development results in the generation of stage‐specific defects

2013

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The vertebrate limb is one of the most intensively studied organs in the field of developmental biology. Limb development in tetrapod vertebrates is highly conserved and dependent on the interaction of several important molecular pathways. The bone morphogenetic protein (BMP) signaling cascade is one of these pathways and has been shown to be crucial for several aspects of limb development. Here, we have used a Xenopus laevis transgenic line, in which expression of the inhibitor Noggin is under the control of the heatshock promoter hsp70 to examine the effects of attenuation of BMP signaling at different stages of limb development. Remarkably different phenotypes were produced at different stages, illustrating the varied roles of BMP in development of the limb. Very early limb buds appeared to be refractory to the effects of BMP attenuation, developing normally in most cases. Ectopic limbs were produced by overexpression of Noggin corresponding to a brief window of limb development at about stage 49/50, as recently described by Christen et al. (2012). Attenuation of BMP signaling in stage 51 or 52 tadpoles lead to a reduction in the number of digits formed, resulting in hypodactyly or ectrodactyly, as well as occasional defects in the more proximal tibiafibula. Finally, inhibition at stage 54 (paddle stage) led to the formation of dramatically shortened digits resulting from loss of distal phalanges. Transcriptome analysis has revealed the possibility that more Nogginsensitive members of the BMP family could be involved in limb development than previously suspected. Our analysis demonstrates the usefulness of heat-shock-driven gene expression as an effective method for inhibiting a developmental pathway at different times during limb development.

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“…34 . Rare and novel autosomal recessive disorders have been widely reported from communities with high consanguinity rates [35][36][37][38][39][40][41][42] , since the main impact of consanguinity is the increased expression of rare autosomal recessive genetic disorders.…”

Section: Health Impact Of Consanguinitymentioning

confidence: 99%

Consanguineous marriages, pearls and perils: Geneva International Consanguinity Workshop Report

Hamamy

Antonarakis

Cavalli-Sforza

et al. 2011

Genetics in Medicine

259

244

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Approximately 1.1 billion people currently live in countries where consanguineous marriages are customary, and among them one in every three marriages is between cousins. Opinions diverge between those warning of the possible health risks to offspring and others who highlight the social benefits of consanguineous marriages. A consanguinity study group of international experts and counselors met at the Geneva International ConsanguinityWorkshop from 3 rd to 7 th May 2010 to discuss the known and presumptive risks and benefits of close kin marriages, and to identify important future areas for research on consanguinity.The group highlighted the importance of evidence-based counselling recommendations for consanguineous marriages, and of undertaking both genomic and social research in defining the various influences and outcomes of consanguinity. Technological advances infor rapid high-throughput genome sequencing (HTS), and for the identification of copy number variants by comparative genomic hybridization (aCGH) offer a significantn unprecedented opportunity to identify genotype-phenotype correlations focusing on autozygosity, the hallmark of consanguinity. The ongoing strong preferential culture of close kin marriages in many societies, and among migrant communities in Western countries, merits an equivalently detailed assessment of the social and genetic benefits of consanguinity in future studies.

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Brachydactyly

Cited by 140 publications

References 51 publications

Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling

Attenuation of bone morphogenetic protein signaling during amphibian limb development results in the generation of stage‐specific defects

Consanguineous marriages, pearls and perils: Geneva International Consanguinity Workshop Report

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