<i>Hox</i> genes in the adult skeleton: Novel functions beyond embryonic development

Rux, Danielle; Wellik, Deneen M.

doi:10.1002/dvdy.24482

Cited by 86 publications

(74 citation statements)

References 96 publications

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“…The Hox family of transcription factors play an important role in the patterning of tissue during development, and some of the Hox genes continue to be expressed in tissues after development (Pineault & Wellik, 2014; Rux & Wellik, 2017). The posterior Hox genes ( Hox9‐13 ), which are involved in patterning of the limb skeleton along the proximodistal axis, were highly expressed in the four tendon types we evaluated (Fig.…”

Section: Resultsmentioning

confidence: 99%

Widespread diversity in the transcriptomes of functionally divergent limb tendons

Disser

Ghahramani

Swanson

et al. 2020

The Journal of Physiology

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Key points Tendon is a hypocellular, matrix‐rich tissue that has been excluded from comparative transcriptional atlases. These atlases have provided important knowledge about biological heterogeneity between tissues, and our study addresses this important gap. We performed measures on four of the most studied tendons, the Achilles, forepaw flexor, patellar and supraspinatus tendons of both mice and rats. These tendons are functionally distinct and are also among the most commonly injured, and therefore of important translational interest. Approximately one‐third of the filtered transcriptome was differentially regulated between Achilles, forepaw flexor, patellar and supraspinatus tendons within either mice or rats. Nearly two‐thirds of the transcripts that are expressed in anatomically similar tendons were different between mice and rats. The overall findings from this study identified that although tendons across the body share a common anatomical definition based on their physical location between skeletal muscle and bone, tendon is a surprisingly genetically heterogeneous tissue. Abstract Tendon is a functionally important connective tissue that transmits force between skeletal muscle and bone. Previous studies have evaluated the architectural designs and mechanical properties of different tendons throughout the body. However, less is known about the underlying transcriptional differences between tendons that may dictate their designs and properties. Therefore, our objective was to develop a comprehensive atlas of the transcriptome of limb tendons in adult mice and rats using systems biology techniques. We selected the Achilles, forepaw digit flexor, patellar, and supraspinatus tendons due to their divergent functions and high rates of injury and tendinopathies in patients. Using RNA sequencing data, we generated the Comparative Tendon Transcriptional Database (CTTDb) that identified substantial diversity in the transcriptomes of tendons both within and across species. Approximately 30% of filtered transcripts were differentially regulated between tendons of a given species, and nearly 60% of the filtered transcripts present in anatomically similar tendons were different between species. Many of the genes that differed between tendons and across species are important in tissue specification and limb morphogenesis, tendon cell biology and tenogenesis, growth factor signalling, and production and maintenance of the extracellular matrix. This study indicates that tendon is a surprisingly heterogenous tissue with substantial genetic variation based on anatomical location and species.

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Section: Resultsmentioning

confidence: 99%

Widespread diversity in the transcriptomes of functionally divergent limb tendons

Disser

Ghahramani

Swanson

et al. 2020

The Journal of Physiology

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“…(26)(27)(28) Importantly, we reported that the adult expression and function of Hox11 genes is spatially restricted to same region in which these genes are expressed and function in the embryo (the zeugopod for Hox11 in the limb skeleton), and that other adult Hox gene expression profiles also follow this pattern in other regions of the skeleton. (25,29) Together, this work suggests that Hox genes are expressed and function with regional specificity in adult skeletal MSCs.…”

Section: Introductionmentioning

confidence: 70%

“…Using a Hoxa11eGFP insertion allele, we demonstrated that Hoxa11eGFP+ cells are exclusively expressed in PDGFRα+, CD51+, and Leptin Receptor+ (LepR+) cells, markers that have been previously characterized to enrich for mesenchymal progenitor activity in bone marrow non‐endothelial stroma and to contribute to fracture healing . Importantly, we reported that the adult expression and function of Hox11 genes is spatially restricted to same region in which these genes are expressed and function in the embryo (the zeugopod for Hox11 in the limb skeleton), and that other adult Hox gene expression profiles also follow this pattern in other regions of the skeleton . Together, this work suggests that Hox genes are expressed and function with regional specificity in adult skeletal MSCs.…”

Section: Introductionmentioning

confidence: 97%

Hox11 Function Is Required for Region-Specific Fracture Repair

Rux

Song

Pineault

et al. 2017

Journal of Bone and Mineral Research

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The processes that govern fracture repair rely on many mechanisms that recapitulate embryonic skeletal development. Hox genes are transcription factors that perform critical patterning functions in regional domains along the axial and limb skeleton during development. Much less is known about roles for these genes in the adult skeleton. We recently reported that Hox11 genes, which function in zeugopod development (radius/ulna and tibia/fibula), are also expressed in the adult zeugopod skeleton exclusively in PDGFRα+/CD51+/LepR+ mesenchymal stem/stromal cells (MSCs). In this study, we use a Hoxa11eGFP reporter allele and loss-of-function Hox11 alleles, and we show that Hox11 expression expands after zeugopod fracture injury, and that loss of Hox11 function results in defects in endochondral ossification and in the bone remodeling phase of repair. In Hox11 compound mutant fractures, early chondrocytes are specified but show defects in differentiation, leading to an overall deficit in the cartilage production. In the later stages of the repair process, the hard callus remains incompletely remodeled in mutants due, at least in part, to abnormal bone matrix organization. Overall, our data supports multiple roles for Hox11 genes following fracture injury in the adult skeleton.

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“…Hox gene expression is critical during skeletal patterning and postnatal bone formation (1)(2)(3). A majority of research in vertebrates has shown that Hox-regulating miRNAs are encoded within the four Hox clusters.…”

Section: Discussionmentioning

confidence: 99%

“…Mammalian homeobox (Hox) 3 developmental transcription factors have diverse roles in bone development and postnatal bone formation (1)(2)(3). These roles include skeletal element formation (4), anterior-posterior homeotic development (4 -10), and limb and axial skeleton formation (11)(12)(13)(14)(15).…”

Section: Micrornas (Mirs) and Hox Transcription Factors Have Decisivementioning

confidence: 99%

The microRNA-23a cluster regulates the developmental HoxA cluster function during osteoblast differentiation

Godfrey

Wildman

Beloti

et al. 2018

Journal of Biological Chemistry

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Edited by Joel GottesfeldMicroRNAs (miRs) and Hox transcription factors have decisive roles in postnatal bone formation and homeostasis. In silico analysis identified extensive interaction between HOXA cluster mRNA and microRNAs from the miR-23a cluster. However, Hox regulation by the miR-23a cluster during osteoblast differentiation remains undefined. We examined this regulation in preosteoblasts and in a novel miR-23a cluster knockdown mouse model. Overexpression and knockdown of the miR-23a cluster in preosteoblasts decreased and increased, respectively, the expression of the proteins HOXA5, HOXA10, and HOXA11; these proteins' mRNAs exhibited significant binding with the miR-23a cluster miRNAs, and miRNA 3-UTR reporter assays confirmed repression. Importantly, during periods correlating with development and differentiation of bone cells, we found an inverse pattern of expression between HoxA factors and members of the miR-23a cluster. HOXA5 and HOXA11 bound to bone-specific promoters, physically interacted with transcription factor RUNX2, and regulated bone-specific genes. Depletion of HOXA5 or HOXA11 in preosteoblasts also decreased cellular differentiation. Additionally, stable overexpression of the miR-23a cluster in osteoblasts decreased the recruitment of HOXA5 and HOXA11 to osteoblast gene promoters, significantly inhibiting histone H3 acetylation. Heterozygous miR-23a cluster knockdown female mice (miR-23a Cl WT/ZIP ) had significantly increased trabecular bone mass when compared with WT mice. Furthermore, miR-23a cluster knockdown in calvarial osteoblasts of these mice increased the recruitment of HOXA5 and HOXA11, with a substantial enrichment of promoter histone H3 acetylation. Taken together, these findings demonstrate that the miR-23a cluster is required for maintaining stagespecific HoxA factor expression during osteogenesis.Mammalian homeobox (Hox) 3 developmental transcription factors have diverse roles in bone development and postnatal bone formation (1-3). These roles include skeletal element formation (4), anterior-posterior homeotic development (4 -10), and limb and axial skeleton formation (11)(12)(13)(14)(15). In fact, cooperation among Hox genes is critical in skeletal development (2, 13, 16 -18). Moreover, Leucht et al. (19) reported that the Hox gene expression status influences the process of adult bone regeneration. A high-throughput ChIP-sequencing study revealed that HOXD13 binds numerous genes that act in key pathways required for early limb and skeletal patterning (20). Furthermore, Wan and Cao (21) reported that a SMAD-HOX association is required to decipher the mechanism of bone morphogenetic protein signaling in osteoblast growth and differentiation. In previous studies, we demonstrated that selective recruitment of HOX transcription factors to bone-specific chromatin at specific stages of osteoblast maturation mediates gene activation (1,(22)(23)(24). Hence, multiple levels of transcriptional and epigenetic regulation by HOX proteins must be examined to define the complete m...

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Hox genes in the adult skeleton: Novel functions beyond embryonic development

Cited by 86 publications

References 96 publications

Widespread diversity in the transcriptomes of functionally divergent limb tendons

Widespread diversity in the transcriptomes of functionally divergent limb tendons

Hox11 Function Is Required for Region-Specific Fracture Repair

The microRNA-23a cluster regulates the developmental HoxA cluster function during osteoblast differentiation

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