Reduced Expression of Thrombospondins and Craniofacial Dysmorphism in Mice Overexpressing Fra1

Nishiwaki, Toru; Yamaguchi, Toru; Zhao, Chen; Amano, Hitoshi; Hankenson, Kurt D.; Börnstein, Paul; Toyama, Yoshiaki; Matsuo, Koichi

doi:10.1359/jbmr.051216

Cited by 18 publications

(22 citation statements)

References 39 publications

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“…It was also reduced by over 75% in the long bones of 3-week-old Fra1 mice. The craniofacial dysmorphism presented by the Fra1 transgenic mice was a skull that was shortened along the anterior-posterior axis and larger along the mediolateral axis as compared to wildtype skulls [35].…”

Section: Discussionmentioning

confidence: 95%

“…Thrombospondins (1 and 2) are expressed in bone and cartilage during development and in the adult skeleton [33]. Although null mutations induced in the mouse do not confer a severe skeletal phenotype, they do result in mild brachygnathism in the double mutant; thbs1−/−, thbs2−/− [34]. THBS2 has also been shown to have implications in craniofacial dysmorphism.…”

Section: Discussionmentioning

confidence: 99%

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Localization of Canine Brachycephaly Using an Across Breed Mapping Approach

et al. 2010

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The domestic dog, Canis familiaris, exhibits profound phenotypic diversity and is an ideal model organism for the genetic dissection of simple and complex traits. However, some of the most interesting phenotypes are fixed in particular breeds and are therefore less tractable to genetic analysis using classical segregation-based mapping approaches. We implemented an across breed mapping approach using a moderately dense SNP array, a low number of animals and breeds carefully selected for the phenotypes of interest to identify genetic variants responsible for breed-defining characteristics. Using a modest number of affected (10–30) and control (20–60) samples from multiple breeds, the correct chromosomal assignment was identified in a proof of concept experiment using three previously defined loci; hyperuricosuria, white spotting and chondrodysplasia. Genome-wide association was performed in a similar manner for one of the most striking morphological traits in dogs: brachycephalic head type. Although candidate gene approaches based on comparable phenotypes in mice and humans have been utilized for this trait, the causative gene has remained elusive using this method. Samples from nine affected breeds and thirteen control breeds identified strong genome-wide associations for brachycephalic head type on Cfa 1. Two independent datasets identified the same genomic region. Levels of relative heterozygosity in the associated region indicate that it has been subjected to a selective sweep, consistent with it being a breed defining morphological characteristic. Genotyping additional dogs in the region confirmed the association. To date, the genetic structure of dog breeds has primarily been exploited for genome wide association for segregating traits. These results demonstrate that non-segregating traits under strong selection are equally tractable to genetic analysis using small sample numbers.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Localization of Canine Brachycephaly Using an Across Breed Mapping Approach

et al. 2010

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“…Bannasch et al (2010) described a haplotype that spans thrombospondin 2 ( THSB2 ), a gene whose product is found in the bone matrix (Young 2003). Mouse studies indicate that together THSB2 and its paralog, THSB1, are required for craniofacial morphogenesis: The anteroposterior axis of Thsb1 −/− Thsb2 −/− mice crania is shorter and its mediolateral axis wider than wild type and single knockouts of either gene alone (Nishiwaki et al 2006). Morphologically, the mouse data appear consistent with CBa.…”

Section: Skull and Axial Skeletonmentioning

confidence: 99%

Insights into Morphology and Disease from the Dog Genome Project

Schoenebeck

Ostrander

2014

Annu. Rev. Cell Dev. Biol.

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Although most modern dog breeds are less than 200 years old, the symbiosis between man and dog is ancient. Since prehistoric times, repeated selection events have transformed the wolf into man’s guardians, laborers, athletes, and companions. The rapid transformation from pack predator to loyal companion is a feat that is arguably unique among domesticated animals. How this transformation came to pass remained a biological mystery until recently: Within the past decade, the deployment of genomic approaches to study population structure, detect signatures of selection, and identify genetic variants that underlie canine phenotypes is ushering into focus novel biological mechanisms that make dogs remarkable. Ironically, the very practices responsible for breed formation also spurned morbidity; today, many diseases are correlated with breed identity. In this review, we discuss man’s best friend in the context of a genetic model to understand paradigms of heritable phenotypes, both desirable and disadvantageous.

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“…Osteoblast differentiation was induced in the presence of 30 g/ml ascorbic acid, 10 mM ␤-glycerophosphate, and 50 ng/ml BMP-2 (R & D Systems). Alkaline phosphatase (ALP) and calcium staining were described previously (15). ALP activity and the amount of calcium were measured using kits (LabAssay TM ALP and calcium C, Wako Pure Chemical Industries) according to the manufacturer's protocols.…”

Section: ϫ7mentioning

confidence: 99%

Bidirectional Signaling through EphrinA2-EphA2 Enhances Osteoclastogenesis and Suppresses Osteoblastogenesis

Irie¹,

Takada²,

Watanabe³

et al. 2009

Journal of Biological Chemistry

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151

166

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Bone is remodeled constantly throughout life by bone-resorbing osteoclasts and bone-forming osteoblasts. To maintain bone volume and quality, differentiation of osteoclasts and osteoblasts is tightly regulated through communication between and within these two cell lineages. Previously we reported that cellcell interaction mediated by ephrinB2 ligand on osteoclasts and EphB4 receptor on osteoblasts generates bidirectional anti-osteoclastogenic and pro-osteoblastogenic signals into respective cells and presumably facilitates transition from bone resorption to bone formation. Here we show that bidirectional ephrinA2-EphA2 signaling regulates bone remodeling at the initiation phase. EphrinA2 expression was rapidly induced by receptor activator of NF-B ligand in osteoclast precursors; this was dependent on the transcription factor c-Fos but independent of the c-Fos target gene product NFATc1. Receptor EphA2 was expressed in osteoclast precursors and osteoblasts. Overexpression experiments revealed that both ephrinA2 and EphA2 in osteoclast precursors enhanced differentiation of multinucleated osteoclasts and that phospholipase C␥2 may mediate ephrinA2 reverse signaling. Moreover, ephrinA2 on osteoclasts was cleaved by metalloproteinases, and ephrinA2 released in the culture medium enhanced osteoclastogenesis. Interestingly, differentiation of osteoblasts lacking EphA2 was enhanced along with alkaline phosphatase, Runx2, and Osterix expression, indicating that EphA2 on osteoblasts generates anti-osteoblastogenic signals presumably by up-regulating RhoA activity. Therefore, ephrinA2-EphA2 interaction facilitates the initiation phase of bone remodeling by enhancing osteoclast differentiation and suppressing osteoblast differentiation.Bone remodeling maintains bone mass constant during adulthood (1, 2). Resorption of old mineralized bone by osteoclasts is followed by new bone formation by osteoblasts. These processes, consisting of the initiation, transition, and termination phases, are tightly regulated by communication between osteoclasts and osteoblasts (3). Bone resorption is excessive in the most common skeletal diseases such as osteoporosis, but molecular mechanisms that balance bone remodeling are only partially understood.Osteoclasts are multinucleated cells (MNCs) 3 responsible for bone resorption. They originate from the fusion of hematopoietic precursor cells of the monocyte/macrophage lineage. Osteoblasts express the two major membrane-bound proteins required for osteoclast differentiation, macrophage-colony stimulating factor (M-CSF), and the receptor activator of NF-B ligand (RANKL). Soluble forms of M-CSF and RANKL allow us to generate osteoclasts from M-CSF-dependent macrophages (MDMs) in cultures. Downstream signaling pathways ultimately activate critical osteoclastogenic transcription factors such as c-Fos (4) and NFATc1 (5-7). NFATc1 is a target gene product of c-Fos (8) and activates gene expression of tartrate-resistant acid phosphatase (TRAP), calcitonin receptor, and ephrinB2.Ephrin ligands and Ep...

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Reduced Expression of Thrombospondins and Craniofacial Dysmorphism in Mice Overexpressing Fra1

Cited by 18 publications

References 39 publications

Localization of Canine Brachycephaly Using an Across Breed Mapping Approach

Localization of Canine Brachycephaly Using an Across Breed Mapping Approach

Insights into Morphology and Disease from the Dog Genome Project

Bidirectional Signaling through EphrinA2-EphA2 Enhances Osteoclastogenesis and Suppresses Osteoblastogenesis

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