MHox: a mesodermally restricted homeodomain protein that binds an essential site in the muscle creatine kinase enhancer

Cserjesi, Peter; Lilly, Brenda; Bryson, Laura; Wang, Yaoqi; Sassoon, David; Olson, Eric N.

doi:10.1242/dev.115.4.1087

Cited by 261 publications

(15 citation statements)

References 63 publications

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“…To achieve this, we crossed Foxf2 f/f mice with Prx1 -Cre mice to generate Foxf2 osp −/− mice. Prx1 is expressed in mesenchymal osteoblast progenitors in limb buds and the craniofacial mesenchyme 27 . Prx1 + cells have also been reported as mesenchymal osteoblast progenitors residing in both the periosteum of cortical bone and the bone marrow in adult mice 28 – 30 .…”

Section: Resultsmentioning

confidence: 99%

Foxf2 represses bone formation via Wnt2b/β-catenin signaling

et al. 2022

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Differentiation of mesenchymal stem cells (MSCs) into osteoblasts is a critical process for proper skeletal development and acquisition/maintenance of bone mass. However, since this regulatory mechanism has not yet been fully elucidated, the treatment of severe osteoporosis and fractures is a challenge. Here, through a comprehensive analysis of gene expression during the differentiation of MSCs into osteoblasts, we show that the forkhead transcription factor Foxf2 is a crucial regulator of this process. Foxf2 expression transiently increased during MSC osteoblastic differentiation. Overexpression of Foxf2 in MSCs inhibited osteoblastic differentiation, and conversely, knockdown of Foxf2 expression promoted this process. Osteoprogenitor-specific Foxf2 knockout mice developed a high bone mass phenotype due to increased bone formation. RNA-seq analysis and molecular experiments revealed that Foxf2 regulation of bone formation is mediated by Wnt2b. Knockdown of Foxf2 in mouse femurs enhanced bone regeneration in vivo. FOXF2 expression was correlated with hip bone mineral density in postmenopausal women with low bone mass. Finally, inhibition of FOXF2 promoted osteoblastic differentiation of human MSCs. This study uncovers a critical role of Foxf2 in the differentiation of MSCs into osteoblasts and provides insight into the pathogenesis associated with bone-related diseases such as osteoporosis and nonunion after fracture.

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Section: Resultsmentioning

confidence: 99%

Foxf2 represses bone formation via Wnt2b/β-catenin signaling

et al. 2022

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“…Some links between the MyoD family and other transcription factors have been suggested. For example, exogenous expression of myogenin induces MEF2 binding activity (19,93), an intact A/T-rich site in the MCK enhancer is required for transactivation of a reporter gene by myogenic HLH proteins (18), and myosin heavy-chain IIB regions that contain MEFi and A/T-rich sites synergistically increase reporter expression when placed together upstream of a basal promoter (78). Since MyoD family members are not expressed in the heart at any time during development (3,44,65,74), the role of E boxes and their putative binding factors in cardiac gene regulation is yet to be established.…”

Section: Discussionmentioning

confidence: 99%

“…5 and 6). Others have shown that an MCK enhancer A/T-rich mutation decreases enhancer activity in skeletal myocytes and prevents transactivation by HLH myogenic regulators in nonmuscle cells (18). A cloned novel homeodomain protein, MHox, that binds this site in vitro is expressed in mesodermal tissues of the mouse embryo and at high levels in adult mouse skeletal muscle, heart, and uterus (18).…”

Section: Sc)mentioning

confidence: 99%

Multiple Regulatory Elements Contribute Differentially to Muscle Creatine Kinase Enhancer Activity in Skeletal and Cardiac Muscle

Amacher

Buskin

Hauschka

1993

Molecular and Cellular Biology

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We have used transient transfections in MM14 skeletal muscle cells, newborn rat primary ventricular myocardiocytes, and nonmuscle cells to characterize regulatory elements of the mouse muscle creatine kinase (MCK) gene. Deletion analysis of MCK 5'-flanking sequence reveals a striated muscle-specific, positive regulatory region between -1256 and -1020. A 206-bp fragment from this region acts as a skeletal muscle enhancer and confers orientation-dependent activity in myocardiocytes. A 110-bp enhancer subfragment confers high-level expression in skeletal myocytes but is inactive in myocardiocytes, indicating that skeletal and cardiac muscle MCK regulatory sites are distinguishable. To further delineate muscle regulatory sequences, we tested six sites within the MCK enhancer for their functional importance. Mutations at five sites decrease expression in skeletal muscle, cardiac muscle, and nonmuscle cells. Mutations at two of these sites, Left E box and MEF2, cause similar decreases in all three cell types. Mutations at three sites have larger effects in muscle than nonmuscle cells; an A/T-rich site mutation has a pronounced effect in both striated muscle types, mutations at the MEF1 (Right E-box) site are relatively specific to expression in skeletal muscle, and mutations at the CArG site are relatively specific to expression in cardiac muscle. Changes at the AP2 site tend to increase expression in muscle cells but decrease it in nonmuscle cells. In contrast to reports involving cotransfection of 10T1/2 cells with plasmids expressing the myogenic determination factor MyoD, we show that the skeletal myocyte activity of multimerized MEF1 sites is 30-fold lower than that of the 206-bp enhancer. Thus, MyoD binding sites alone are not sufficient for high-level expression in skeletal myocytes containing endogenous levels of MyoD and other myogenic determination factors.

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“…Similarly, Osterix (Osx) + cells reside in bone marrow stroma during fetal development, and further form perivascular, osteogenic, and adipogenic cells [ 25 , 34 ]. Prx1 is highly expressed by limb bud mesenchymal progenitors during long bone development [ 35 ], and genetic lineage tracing by Prx1-Cre labels all skeletal lineage cells in long bones, including skeletal stem/progenitor cells (SSPCs), osteoblasts, osteocytes, chondrocytes, and adipocytes [ 36 ].…”

Section: Functional Heterogeneity Of Bmsc Subpopulations In Physiolog...mentioning

confidence: 99%

Functional Heterogeneity of Bone Marrow Mesenchymal Stem Cell Subpopulations in Physiology and Pathology

Ning

Chen

et al. 2022

IJMS

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Bone marrow mesenchymal stem cells (BMSCs) are multi-potent cell populations and are capable of maintaining bone and body homeostasis. The stemness and potential therapeutic effect of BMSCs have been explored extensively in recent years. However, diverse cell surface antigens and complex gene expression of BMSCs have indicated that BMSCs represent heterogeneous populations, and the natural characteristics of BMSCs make it difficult to identify the specific subpopulations in pathological processes which are often obscured by bulk analysis of the total BMSCs. Meanwhile, the therapeutic effect of total BMSCs is often less effective partly due to their heterogeneity. Therefore, understanding the functional heterogeneity of the BMSC subpopulations under different physiological and pathological conditions could have major ramifications for global health. Here, we summarize the recent progress of functional heterogeneity of BMSC subpopulations in physiology and pathology. Targeting tissue-resident single BMSC subpopulation offers a potentially innovative therapeutic strategy and improves BMSC effectiveness in clinical application.

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MHox: a mesodermally restricted homeodomain protein that binds an essential site in the muscle creatine kinase enhancer

Cited by 261 publications

References 63 publications

Foxf2 represses bone formation via Wnt2b/β-catenin signaling

Foxf2 represses bone formation via Wnt2b/β-catenin signaling

Multiple Regulatory Elements Contribute Differentially to Muscle Creatine Kinase Enhancer Activity in Skeletal and Cardiac Muscle

Functional Heterogeneity of Bone Marrow Mesenchymal Stem Cell Subpopulations in Physiology and Pathology

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