Hox5
 interacts with
 Plzf
 to restrict
 Shh
 expression in the developing forelimb

Xu, Ben; Hrycaj, Steven; McIntyre, Daniel C.; Baker, Nicholas C.; Takeuchi, Jun; Jeannotte, Lucie; Gaber, Zachary B.; Novitch, Bennett G.; Wellik, Deneen M.

doi:10.1073/pnas.1315075110

Cited by 45 publications

(47 citation statements)

References 59 publications

(83 reference statements)

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“…ZBTB16 is a negative regulator of cell division in embryogenesis and controls skeletal patterning through repression of HOX, BMP, and Sonic Hedge Hog (Shh) expression. Deletion of ZBTB16 in mice leads to severe skeletal deformities due to impaired limb and axial skeleton patterning leading to transformation of anterior skeletal elements into posterior structures [41][42][43]. ZBTB16 is required for stylopod and zeugopod formation during early stages of limb development, before the initiation of cartilage condensation [44].…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

Hemming

Cakouros

Vandyke

et al. 2016

Stem Cells and Development

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Histone three lysine 27 (H3K27) methyltransferase enhancer of zeste homolog 2 (EZH2) is a critical epigenetic modifier, which regulates gene transcription through the trimethylation of the H3K27 residue leading to chromatin compaction and gene repression. EZH2 has previously been identified to regulate human bone marrow-derived mesenchymal stem cells (MSC) lineage specification. MSC lineage specification is regulated by the presence of EZH2 and its H3K27me3 modification or the removal of the H3K27 modification by lysine demethylases 6A and 6B (KDM6A and KDM6B). This study used a bioinformatics approach to identify novel genes regulated by EZH2 during MSC osteogenic differentiation. In this study, we identified the EZH2 targets, ZBTB16, MX1, and FHL1, which were expressed at low levels in MSC. EZH2 and H3K27me3 were found to be present along the transcription start site of their respective promoters. During osteogenesis, these genes become actively expressed coinciding with the disappearance of EZH2 and H3K27me3 on the transcription start site of these genes and the enrichment of the active H3K4me3 modification. Overexpression of EZH2 downregulated the transcript levels of ZBTB16, MX1, and FHL1 during osteogenesis. Small interfering RNA targeting of MX1 and FHL1 was associated with a downregulation of the key osteogenic transcription factor, RUNX2, and its downstream targets osteopontin and osteocalcin. These findings highlight that EZH2 not only acts through the direct regulation of signaling modules and lineage-specific transcription factors but also targets many novel genes important for mediating MSC osteogenic differentiation.

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Section: Discussionmentioning

confidence: 99%

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

Hemming

Cakouros

Vandyke

et al. 2016

Stem Cells and Development

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“…Sophisticated genetic experiments in which mouse embryos were produced that lacked all Hox5 function showed that their activity is required for the development of the anterior region of the forelimb bud (Xu et al. ). Similar experiments in which the function of all the Hox9 paralogous genes was inactivated showed that Hox9 activity is required for the development of the posterior region of the forelimb bud (Xu & Wellik, ).…”

Section: Determination Of Limb Antero‐posterior Polaritymentioning

confidence: 99%

How the embryo makes a limb: determination, polarity and identity

2015

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The vertebrate limb with its complex anatomy develops from a small bud of undifferentiated mesoderm cells encased in ectoderm. The bud has its own intrinsic polarity and can develop autonomously into a limb without reference to the rest of the embryo. In this review, recent advances are integrated with classical embryology, carried out mainly in chick embryos, to present an overview of how the embryo makes a limb bud. We will focus on how mesoderm cells in precise locations in the embryo become determined to form a limb and express the key transcription factors Tbx4 (leg/hindlimb) or Tbx5 (wing/forelimb). These Tbx transcription factors have equivalent functions in the control of bud formation by initiating a signalling cascade involving Wnts and fibroblast growth factors (FGFs) and by regulating recruitment of mesenchymal cells from the coelomic epithelium into the bud. The mesoderm that will form limb buds and the polarity of the buds is determined with respect to both anteroposterior and dorso-ventral axes of the body. The position in which a bud develops along the antero-posterior axis of the body will also determine its identity -wing/forelimb or leg/hindlimb. Hox gene activity, under the influence of retinoic acid signalling, is directly linked with the initiation of Tbx5 gene expression in the region along the antero-posterior axis of the body that will form wings/forelimbs and determines antero-posterior polarity of the buds. In contrast, Tbx4 expression in the regions that will form legs/hindlimbs is regulated by the homeoprotein Pitx1 and there is no evidence that Hox genes determine antero-posterior polarity of the buds. Bone morphogenetic protein (BMP) signalling determines the region along the dorso-ventral axis of the body in which both wings/forelimbs and legs/hindlimbs develop and dorso-ventral polarity of the buds. The polarity of the buds leads to the establishment of signalling regions -the dorsal and ventral ectoderm, producing Wnts and BMPs, respectively, the apical ectodermal ridge producing fibroblast growth factors and the polarizing region, Sonic hedgehog (Shh). These signals are the same in both wings/forelimbs and legs/hindlimbs and control growth and pattern formation by providing the mesoderm cells of the limb bud as it develops with positional information. The precise anatomy of the limb depends on the mesoderm cells in the developing bud interpreting positional information according to their identity -determined by Pitx1 in hindlimbs -and genotype. The competence to form a limb extends along the entire antero-posterior axis of the trunk -with Hox gene activity inhibiting the formation of forelimbs in the interlimb region -and also along the dorso-ventral axis.

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“…This results in only one skeletal element in each limb segment, identical to the phenotype resulting from loss of Shh function [29]. Loss-of-function mutations in the Hox5 paralogous group ( Hoxa5 −/−, Hoxb5 −/−, Hoxc5 −/− ) results in loss of repression of anterior Shh expression in the anterior limb bud leading to anterior patterning defects in the limb [30]. In this case, Hox5 has been reported to interact with Plzf and functions to restrict Shh to the posterior limb bud [30].…”

Section: Hox Function and Skeletal Patterningmentioning

confidence: 99%

Hox Genes and Limb Musculoskeletal Development

Pineault

Wellik

2014

Curr Osteoporos Rep

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In the musculoskeletal system, muscle, tendon and bone tissues develop in a spatially and temporally coordinated manner, and integrate into a cohesive functional unit by forming specific connections unique to each region of the musculoskeletal system. The mechanisms of these patterning and integration events are an area of great interest in musculoskeletal biology. Hox genes are a family of important developmental regulators and play critical roles in skeletal patterning throughout the axial and appendicular skeleton. Unexpectedly, Hox genes are not expressed in the differentiated cartilage or other skeletal cells, but rather are highly expressed in the tightly associated stromal connective tissues as well as regionally expressed in tendons and muscle connective tissue. Recent work has revealed a previously unappreciated role for Hox in patterning all the musculoskeletal tissues of the limb. These observations suggest that integration of the musculoskeletal system is regulated, at least in part, by Hox function in the stromal connective tissue. This review will outline our current understanding of Hox function in patterning and integrating the musculoskeletal tissues.

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Hox5 interacts with Plzf to restrict Shh expression in the developing forelimb

Cited by 45 publications

References 59 publications

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

How the embryo makes a limb: determination, polarity and identity

Hox Genes and Limb Musculoskeletal Development

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