<i>Hox10</i>
            and
            <i>Hox11</i>
            Genes Are Required to Globally Pattern the Mammalian Skeleton

Wellik, Deneen M.; Capecchi, Mario R.

doi:10.1126/science.1085672

Cited by 538 publications

(542 citation statements)

References 19 publications

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“…One mechanism by which this might be accomplished is via Hox gene expression, and we took cues from the developmental expression pattern of Hox genes to focus our analyses. Limb mesenchyme destined to form the tibiae expresses a number of Hox genes including Hox11 (Wellik and Capecchi, 2003), and we found that Hoxa11 expression persisted in adult tibial osteoblasts and osteocytes (Fig. 6).…”

Section: Research Articlementioning

confidence: 73%

“…During development, Hox genes are expressed in a nested pattern along the body axis (Chisaka and Capecchi, 1991;Creuzet et al, 2002;Wellik and Capecchi, 2003;Le Douarin et al, 2004), where they provide cells with positional information. For example, Hoxa11 and Hoxa13 are expressed in limb mesoderm (Wellik and Capecchi, 2003;Knosp et al, 2004;Rinn et al, 2008), where they regulate patterning and morphogenesis of the fetal appendicular skeleton (Tabin, 1995).…”

Section: An Association Between Embryonic Lineage and Hox Status Mighmentioning

confidence: 99%

“…For example, Hoxa11 and Hoxa13 are expressed in limb mesoderm (Wellik and Capecchi, 2003;Knosp et al, 2004;Rinn et al, 2008), where they regulate patterning and morphogenesis of the fetal appendicular skeleton (Tabin, 1995). Are adult cells provided with positional memory through a similar molecular mechanism?…”

Section: An Association Between Embryonic Lineage and Hox Status Mighmentioning

confidence: 99%

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Embryonic origin and Hox status determine progenitor cell fate during adult bone regeneration

et al. 2008

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The fetal skeleton arises from neural crest and from mesoderm. Here, we provide evidence that each lineage contributes a unique stem cell population to the regeneration of injured adult bones. Using Wnt1Cre::Z/EG mice we found that the neural crest-derived mandible heals with neural crest-derived skeletal stem cells, whereas the mesoderm-derived tibia heals with mesoderm-derived stem cells. We tested whether skeletal stem cells from each lineage were functionally interchangeable by grafting mesodermderived cells into mandibular defects, and vice versa. All of the grafting scenarios, except one, healed through the direct differentiation of skeletal stem cells into osteoblasts; when mesoderm-derived cells were transplanted into tibial defects they differentiated into osteoblasts but when transplanted into mandibular defects they differentiated into chondrocytes. A mismatch between the Hox gene expression status of the host and donor cells might be responsible for this aberration in bone repair. We found that initially, mandibular skeletal progenitor cells are Hox-negative but that they adopt a Hoxa11-positive profile when transplanted into a tibial defect. Conversely, tibial skeletal progenitor cells are Hox-positive and maintain this Hox status even when transplanted into a Hox-negative mandibular defect. Skeletal progenitor cells from the two lineages also show differences in osteogenic potential and proliferation, which translate into more robust in vivo bone regeneration by neural crest-derived cells. Thus, embryonic origin and Hox gene expression status distinguish neural crest-derived from mesoderm-derived skeletal progenitor cells, and both characteristics influence the process of adult bone regeneration.

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Section: Research Articlementioning

confidence: 73%

Section: An Association Between Embryonic Lineage and Hox Status Mighmentioning

confidence: 99%

Section: An Association Between Embryonic Lineage and Hox Status Mighmentioning

confidence: 99%

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Embryonic origin and Hox status determine progenitor cell fate during adult bone regeneration

et al. 2008

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“…Curiously, a distally shifted third trochanter and ectopic ligament is also found in Hoxa10 −/− mice, and the Dkk1 d/− femora are remarkably similar to the mildly affected Hoxa10 −/− mice on an inbred 129/Sv background [45]. The paralogous Hox10 genes are responsible for patterning the stylopod and stylopod/zeugopod junction (elbow and knee joints), particularly in the hindlimb [47]. Favier et al speculate that the ectopic ligament in Hoxa10 −/− originates from a thickening of the septum intermuscularis femoris lateralis, and the abnormal thickening of this structure may be due to the antagonistic tensions between the gastocnemius and the gluteus superficialis muscles [45].…”

Section: Discussionmentioning

confidence: 99%

Bone mass is inversely proportional to Dkk1 levels in mice

MacDonald

Joiner

Oyserman

et al. 2007

Bone

156

106

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The Wnt/β-catenin signaling pathway has emerged as a key regulator in bone development and bone homeostasis. Loss-of-function mutations in the Wnt co-receptor LRP5 result in osteoporosis and "activating" mutations in LRP5 result in high bone mass. Dickkopf-1 (DKK1) is a secreted Wnt inhibitor that binds LRP5 and LRP6 during embryonic development, therefore it is expected that a decrease in DKK1 will result in an increase in Wnt activity and a high bone mass phenotype. Dkk1 −/− knockout mice are embryonic lethal, but mice with hypomorphic Dkk1 d (doubleridge) alleles that express low amounts of Dkk1 are viable. In this study we generated an allelic series by crossing Dkk1 +/− and Dkk1 +/d mice resulting in the following genotypes with decreasing Dkk1 expression levels: +/+, +/d, +/− and d/−. Using μCT imaging we scanned dissected left femora and calvariae from eight week old mice (n=60). We analyzed the distal femur to represent trabecular bone and the femur diaphysis for cortical endochondral bone. A region of the parietal bones was used to analyze intramembranous bone of the calvaria. We found that trabecular bone volume is increased in Dkk1 mutant mice in a manner that is inversely proportional to the level of Dkk1 expression. Trabeculae number and thickness were significantly higher in the low Dkk1 expressing genotypes from both female and male mice. Similar results were found in cortical bone with an increase in cortical thickness and cross sectional area of the femur diaphysis that correlated with lower Dkk1 expression. No consistent differences were found in the calvaria measurements. Our results indicate that the progressive Dkk1 reduction increases trabecular and cortical bone mass and that even a 25% reduction in Dkk1 expression could produce significant increases in trabecular bone volume fraction. Thus DKK1 is a negative regulator of normal bone homeostasis in vivo. Our study suggests that manipulation of DKK1 function or expression may have therapeutic significance for the treatment of low bone mass disorders.

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“…Numerous reports have shown that alterations in Hox gene expression result in anteriorization or posteriorization of the vertebral column and rib cage, and some of these mutants show a shift in limb position (Horan et al, 1995;Rancourt et al, 1995;Cohn et al, 1997;Chen et al, 1998; van den Akker Developmental Dynamics Wellik and Capecchi, 2003;McIntyre et al, 2007;Wellik, 2007, and references therein). It is, however, unclear if Hox genes in the paraxial mesoderm are responsible for limb field specification, because they are also expressed in other tissues, including the LPM itself (Burke et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Role of paraxial mesoderm in limb/flank regionalization of the trunk lateral plate

Noro

Yuguchi

Sato

et al. 2011

Developmental Dynamics

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To understand the developmental mechanism that determines limb size and the consequent limb-to-trunk proportions in the tetrapod body, we investigated the role of the paraxial mesoderm in the specification of the limb and flank fields in the chick embryo. We found that the paraxial mesoderm subjacent to the limb field can affect the size of the limb bud along the anterior-posterior and proximal-distal axes. We also found that the paraxial mesoderm subjacent to the flank plays roles in suppressing the emergence and growth of the limb bud and in promoting flank-specific apoptosis in the lateral plate mesoderm. Our results suggest that signals from the paraxial mesoderm specify the limb and flank fields in the competent lateral plate mesoderm.

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Hox10 and Hox11 Genes Are Required to Globally Pattern the Mammalian Skeleton

Cited by 538 publications

References 19 publications

Embryonic origin and Hox status determine progenitor cell fate during adult bone regeneration

Embryonic origin and Hox status determine progenitor cell fate during adult bone regeneration

Bone mass is inversely proportional to Dkk1 levels in mice

Role of paraxial mesoderm in limb/flank regionalization of the trunk lateral plate

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