Yuji Mishina

Kinki University, Ōsaka, Ōsaka, Japan

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Publications (174)1098.76 Total impact

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    ABSTRACT: Transforming growth factor-beta3 (TGF-β3) plays a critical role in palatal epithelial cells by inducing palatal epithelial fusion, failure of which results in cleft palate, one of the most common birth defects in humans. Recent studies have shown that Smad-dependent and Smad-independent pathways work redundantly to transduce TGF-β3 signaling in palatal epithelial cells. However, detailed mechanisms by which this signaling is mediated still remain to be elucidated. Here we show that TGF-β activated kinase-1 (Tak1) and Smad4 interact genetically in palatal epithelial fusion. While simultaneous abrogation of both Tak1 and Smad4 in palatal epithelial cells resulted in characteristic defects in the anterior and posterior secondary palate, these phenotypes were less severe than those seen in the corresponding Tgfb3 mutants. Moreover, our results demonstrate that Trim33, a novel chromatin reader and regulator of TGF-β signaling, cooperates with Smad4 during palatogenesis. Unlike the epithelium-specific Smad4 mutants, epithelium-specific Tak1:Smad4- and Trim33:Smad4-double mutants display reduced expression of Mmp13 in palatal medial edge epithelial cells, suggesting that both of these redundant mechanisms are required for appropriate TGF-β signal transduction. Moreover, we show that inactivation of Tak1 in Trim33:Smad4 double conditional knockouts leads to the palatal phenotypes which are identical to those seen in epithelium-specific Tgfb3 mutants. To conclude, our data reveal added complexity in TGF-β signaling during palatogenesis and demonstrate that functionally redundant pathways involving Smad4, Tak1 and Trim33 regulate palatal epithelial fusion.
    Developmental Biology 12/2014; · 3.64 Impact Factor
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    ABSTRACT: Platelet-derived growth factors (PDGFs) play important roles in skeletal development and bone fracture healing, yet how PDGFs execute their functions remains incompletely understood. Here we show that PDGF-AA, but not -AB or -BB, could activate the BMP-Smad1/5/8 pathway in mesenchymal stem cells (MSCs), which requires BMPRIA as well as PDGFRα. PDGF-AA promotes MSC osteogenic differentiation through the BMP-Smad1/5/8-Runx2/Osx axis and MSC migration via the BMP-Smad1/5/8-Twist1/Atf4 axis. Mechanistic studies show that PDGF-AA activates BMP-Smad1/5/8 signaling by feedback down-regulating PDGFRα, which frees BMPRI and allows for BMPRI-BMPRII complex formation to activate smad1/5/8, using BMP molecules in the microenvironment. This study unravels a physical and functional interaction between PDGFRα and BMPRI, which plays an important role in MSC differentiation and migration, and establishes a link between PDGF-AA and BMPs pathways, two essential regulators of embryonic development and tissue homeostasis.
    PLoS ONE 12/2014; 9(12):e113785. · 3.53 Impact Factor
  • Taylor Nicholas Snider, Yuji Mishina
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    ABSTRACT: This review provides an overview of the state and future directions of development and pathology in the craniofacial complex in the context of Cranial Neural Crest Cells (CNCC). CNCC are a multipotent cell population that is largely responsible for forming the vertebrate head. We focus on findings that have increased the knowledge of gene regulatory networks and molecular mechanisms governing CNCC migration and the participation of these cells in tissue formation. Pathology due to aberrant migration or cell death of CNCC, termed neurocristopathies, is discussed in addition to craniosynostoses. Finally, we discuss tissue engineering applications that take advantage of recent advancements in genome editing and the multipotent nature of CNCC. These applications have relevance to treating diseases due directly to the failure of CNCC, and also in restoring tissues lost due to a variety of reasons. Birth Defects Research (Part C), 2014. © 2014 Wiley Periodicals, Inc.
    Birth Defects Research Part C Embryo Today Reviews 09/2014; · 4.44 Impact Factor
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    ABSTRACT: Abstract The importance of Bone Morphogenetic Proteins (BMPs) in the regulation of cell fate, differentiation and proliferation in the growth plate is well-known. However, in secondary cartilages (such as that in the temporomandibular joint) that grow by proliferation of prechondrocytes and differ in their pattern of growth, the role of BMPs is largely unexplored. To examine this question, we ablated Bmpr1a in the condylar cartilage of neonatal mice and assessed the consequences for mandibular condyle growth and organization at intervals over the ensuing 4 weeks. Bmpr1a deficiency caused significant chondrodysplasia and almost eliminated the chondrocytic phenotype in the TMJ. Expression of Sox9, collagen II, proteoglycan were all greatly reduced, and cell proliferation as detected by BrdU was almost non-existent in the knockout mice. Primary bone spongiosa formation was also disturbed and was accompanied by reduced Osterix expression. These findings strongly suggest that Bmpr1a is critical for the development and growth of the mandibular condyle via its effect on proliferation of prechondroblasts and chondrocyte differentiation.
    Connective Tissue Research 08/2014; 55(S1):73-78. · 1.98 Impact Factor
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    ABSTRACT: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play significant roles in vertebrate organogenesis and morphogenesis. FGFR3 is a negative regulator of chondrogenesis and multiple mutations with constitutive activity of FGFR3 result in achondroplasia, one of the most common dwarfisms in humans, but the molecular mechanism remains elusive. In this study, we found that chondrocyte-specific deletion of BMP type I receptor a (Bmpr1a) rescued the bone overgrowth phenotype observed in Fgfr3 deficient mice by reducing chondrocyte differentiation. Consistently, using in vitro chondrogenic differentiation assay system, we demonstrated that FGFR3 inhibited BMPR1a-mediated chondrogenic differentiation. Furthermore, we showed that FGFR3 hyper-activation resulted in impaired BMP signaling in chondrocytes of mouse growth plates. We also found that FGFR3 inhibited BMP-2- or constitutively activated BMPR1-induced phosphorylation of Smads through a mechanism independent of its tyrosine kinase activity. We found that FGFR3 facilitate BMPR1a to degradation through Smurf1-mediated ubiquitination pathway. We demonstrated that down-regulation of BMP signaling by BMPR1 inhibitor dorsomorphin led to the retardation of chondrogenic differentiation, which mimicks the effect of FGF-2 on chondrocytes and BMP-2 treatment partially rescued the retarded growth of cultured bone rudiments from thanatophoric dysplasia type II mice. Our findings reveal that FGFR3 promotes the degradation of BMPR1a, which plays an important role in the pathogenesis of FGFR3-related skeletal dysplasia.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 07/2014; · 5.30 Impact Factor
  • Yuji Mishina, Taylor Nicholas Snider
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    ABSTRACT: Neural crest cells appear early during embryogenesis and give rise to many structures in the mature adult. In particular, a specific population of neural crest cells migrates to and populates developing cranial tissues. The ensuing differentiation of these cells via individually complex and often intersecting signaling pathways is indispensible to growth and development of the craniofacial complex. Much research has been devoted to this area of development with particular emphasis on cell signaling events required for physiologic development. Understanding such mechanisms will allow researchers to investigate ways in which they can be exploited in order to treat a multitude of diseases affecting the craniofacial complex. Knowing how these multipotent cells are driven towards distinct fates could, in due course, allow patients to receive regenerative therapies for tissues lost to a variety of pathologies. In order to realize this goal, nucleotide sequencing advances allowing snapshots of entire genomes and exomes are being utilized to identify molecular entities associated with disease states. Once identified, these entities can be validated for biological significance with other methods. A crucial next step is the integration of knowledge gleaned from observations in disease states with normal physiology to generate an explanatory model for craniofacial development. This review seeks to provide a current view of the landscape on cell signaling and fate determination of the neural crest and to provide possible avenues of approach for future research.
    Experimental Cell Research 07/2014; · 3.37 Impact Factor
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    ABSTRACT: The molecular mechanisms of endothelial dysfunction and vascular calcification have been considered independently and potential links are currently unknown in chronic kidney disease (CKD). Bone morphogenetic protein (BMP) receptor signaling mediates calcification of atherosclerotic plaques. Here we tested whether BMP receptor signaling contributes to endothelial dysfunction, as well as to osteogenic differentiation of vascular smooth muscle cells (VSMCs), in a model of short-term CKD. In C57BL/6 mice, subtotal nephrectomy activated BMP receptor and increased phosphatase-and-tensin homolog (PTEN) protein in the endothelial cells and medial VSMCs without vascular remodeling in the aorta. In the endothelial cells, PTEN induction led to inhibition of the Akt-endothelial nitric oxide synthase (eNOS) pathway and endothelial dysfunction. In VSMCs, the PTEN increase induced early osteogenic differentiation. CKD-induced inhibition of eNOS phosphorylation and the resultant endothelial dysfunction were inhibited in mice with endothelial cell-specific PTEN ablation. Knockout of the BMP type I receptor abolished endothelial dysfunction, the inhibition of eNOS phosphorylation, and VSMC osteogenic differentiation in mice with CKD. A small molecule inhibitor of BMP type I receptor, LDN-193189, prevented endothelial dysfunction and osteogenic differentiation in CKD mice. Thus, BMP receptor activation is a mechanism for endothelial dysfunction in addition to vascular osteogenic differentiation in a short-term CKD model. PTEN may be key in linking BMP receptor activation and endothelial dysfunction in CKD.Kidney International advance online publication, 25 June 2014; doi:10.1038/ki.2014.223.
    Kidney International 06/2014; · 8.52 Impact Factor
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    ABSTRACT: BMP signaling plays an essential role in second heart field-derived heart and arterial trunk development, including myocardial differentiation, right ventricular growth, and interventricular, outflow tract and aortico-pulmonary septation. It is mediated by a number of different BMP ligands, and receptors, many of which are present simultaneously. The mechanisms by which they regulate morphogenetic events and degree of redundancy amongst them have still to be elucidated. We therefore assessed the role of BMP Type I receptor AcvR1 in anterior second heart field-derived cell development, and compared it with that of BmpR1a. By removing Acvr1 using the driver Mef2c[AHF]-Cre, we show that AcvR1 plays an essential role in arterial pole morphogenesis, identifying defects in outflow tract wall and cushion morphology that preceded a spectrum of septation defects from double outlet right ventricle to common arterial trunk in mutants. Its absence caused dysregulation in gene expression important for myocardial differentiation (Isl1, Fgf8) and regional identity (Tbx2, Tbx3, Tbx20, Tgfb2). Although these defects resemble to some degree those in the equivalent Bmpr1a mutant, a novel gene knock-in model in which Bmpr1a was expressed in the Acvr1 locus only partially restored septation in Acvr1 mutants. These data show that both BmpR1a and AcvR1 are needed for normal heart development, in which they play some non-redundant roles, and refine our understanding of the genetic and morphogenetic processes underlying Bmp-mediated heart development important in human congenital heart disease.
    Developmental Biology 06/2014; · 3.64 Impact Factor
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    ABSTRACT: Background: Oral symptoms of Ellis-van Creveld (EvC) syndrome, an autosomal recessive skeletal dysplasia, include anodontia, enamel hypoplasia, conical shaped teeth, and malocclusion. Because affected individuals have nonsense mutations in one of two conserved genes (EVC or EVC2), we previously investigated the disorder and its associated craniofacial phenotype by generating a global knockout (KO) mouse model for Evc2 that phenocopied the oral symptoms of EvC patients. Objective: The systemic incidence of mutation hinders the investigation of cell lineage-specific phenotypic outcomes. Due to the prevalence of neural crest cell (NCC)-derived structures within the craniofacial region, we developed a conditional mutant mouse model whereby Evc2 was specifically knocked out in NCC and characterized the resultant phenotype. Methods: The P0 promoter was used to generate NCC-specific Evc2 knockout mice (cKO) via Cre-lox recombination. Control and Evc2 cKO specimens underwent cranial µCT and lateral histomorphometric analysis at postnatal day 8 (n=29) and day 28 (n=17). Results: Evc2 cKO mice at postnatal day 8 (P8) exhibited delayed lower incisor eruption and significantly reduced cranial base and total skull lengths. cKO mice at postnatal day 28 (P28) showed significant morphometric reductions of the following: neurocranium, viscerocranium, nasal bone, mandibular corpus, and total skull. Additionally, cKO mice at P28 had bifurcated roots on their mandibular first molars. Morphometric differences observed in cKO mice at P28, though more severe and widespread than those seen in P8 cKO specimens, were consistent and comparable to global KO models. Conclusions: NCC-specific knock out of Evc2 results in a craniofacial phenotype present at P8 and P28. Affected specimens are smaller than their control littermates and phenotypic differences are more severe at P28 than P8.
    AADR Annual Meeting & Exhibition 2014; 03/2014
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    ABSTRACT: Background: Ellis-van Creveld (EvC) syndrome is a rare chondro-ectodermal dysplasia with an autosomal recessive trait affecting bone and cartilage growth. EvC patients have mutations in either EVC or EVC2 gene, both of which are located on chromosome 4 in a head-to-head configuration. Objective: There were several cases reported that abnormal craniofacial bone phenotype was observed in EvC patients; however, it is currently unknown whether mutation of EVC or EVC2 gene causes such craniofacial bone phenotypes. Our objective is to investigate and characterize the craniofacial phenotype using Evc2 knockout (KO) mice. Methods: Evc2 KO mice were used in this study as an animal model of EvC syndrome and craniofacial bone development/phenotype in these mice was investigated in comparison to controls, i.e. wild type and heterozygous mice. Lateral cephalometric radiographs and analysis were conducted on three postnatal groups [one (n=15), three (n=11), and six (n=9) weeks old]. The expression pattern of Evc2 was investigated; in addition, onset and levels of both proliferation and apoptosis in chondrocytes were identified in the developing embryos [E15.5-E18.5]. Results: Our data showed that the postnatal bone growth deficiency in KO mice was found in areas where expression of Evc2 was observed. Growth rate of craniofacial bones in KO mice was reduced to 72-79 % of that of controls at the tested time points. Notably, growth of certain bones including nasal bone, palatal bone and premaxilla was more affected in KO than in the controls. Furthermore, there was a remarkable change in facial bones’ spatial relationship to the cranial base and vault. We also found an earlier onset of apoptosis and proliferation defects in chondrocytes in KO compared to controls. Conclusions: Evc2 is required for craniofacial bone development and deficiency in Evc2 leads to specific facial bone growth defect due to imbalance of cellular proliferation and cell death.
    AADR Annual Meeting & Exhibition 2014; 03/2014
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    ABSTRACT: In situ hybridization is a powerful method for detecting endogenous mRNA sequences in morphologically preserved samples. We provide in situ hybridization methods, which are specifically optimized for mouse embryonic samples as whole mounts and section tissues. Additionally, β-Galactosidase (β-gal) is a popular reporter for detecting the expression of endogenous or exogenous genes. We reveal that 6-chloro-3-indoxyl-β-D-galactopyranoside (S-gal) is a more sensitive substrate for β-gal activity than 5-bromo-4-chloro-3-indolyl-β-D-galactoside (X-gal). S-gal is advantageous where β-gal activity is limited including early stage mouse embryos. As a result of the increased sensitivity as well as the color compatibility of S-gal, we successfully combined β-gal staining using S-gal with in situ hybridization using DIG-labeled probes in both whole mounts and sections.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1092:1-15. · 1.29 Impact Factor
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    ABSTRACT: Dendrite development is controlled by the interplay of intrinsic and extrinsic signals affecting initiation, growth, and maintenance of complex dendrites. Bone morphogenetic proteins (BMPs) stimulate dendrite growth in cultures of sympathetic, cortical, and hippocampal neurons but it was unclear whether BMPs control dendrite morphology in vivo. Using a conditional knock-out strategy to eliminate Bmpr1a and Smad4 in immature noradrenergic sympathetic neurons we now show that dendrite length, complexity, and neuron cell body size are reduced in adult mice deficient of Bmpr1a. The combined deletion of Bmpr1a and Bmpr1b causes no further decrease in dendritic features. Sympathetic neurons devoid of Bmpr1a/1b display normal Smad1/5/8 phosphorylation, which suggests that Smad-independent signaling paths are involved in dendritic growth control downstream of BMPR1A/B. Indeed, in the Smad4 conditional knock-out dendrite and cell body size are not affected and dendrite complexity and number are increased. Together, these results demonstrate an in vivo function for BMPs in the generation of mature sympathetic neuron dendrites. BMPR1 signaling controls dendrite complexity postnatally during the major dendritic growth period of sympathetic neurons.
    Journal of Neuroscience 09/2013; 33(38):15132-15144. · 6.75 Impact Factor
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    ABSTRACT: Abstract Background: Hyperoxia or clinical oxygen (O2) therapy is known to result in increased oxidative burden. Therefore, understanding susceptibility to hyperoxia exposure is clinically important. Bone morphogenetic proteins (BMPs) 2 and 4 are involved in cardiac development and may influence responses to hyperoxia. Methods. Bmp2(+/)(-). Bmp4(+/)(-) and wild-type mice were exposed to hyperoxia (100% O2) for 24 hrs. Electrocardiograms (ECG) were recorded before and during exposure by radio-telemetry. Results: At baseline, a significantly higher low frequency (LF) and total power (TP) heart rate variability (HRV) were found in Bmp2(+/)(-) mice only (p < 0.05). Twenty-four hours hyperoxia-induced strain-independent reductions in heart rate, QTcB and ST-interval and increases in QRS, LF HRV and standard deviation of RR-intervals were observed. In Bmp4(+/)(-) mice only, increased PR-interval (PR-I) (24 hrs), P-wave duration (P-d; 18 and 21-24 hrs), PR-I minus P-d (PR - Pd; 24 hrs) and root of the mean squared differences of successive RR-intervals (24 hrs) were found during hyperoxia (p < 0.05). Discussion: Elevated baseline LF and TP HRV in Bmp2(+/)(-) mice suggests an altered autonomic nervous system regulation of cardiac function in these mice. However, this was not related to strain specific differences in responses to 24 hrs hyperoxia. During hyperoxia, Bmp4(+/-) mice were the most susceptible in terms of atrioventricular conduction changes and risk of atrial fibrillation, which may have important implications for patients treated with O2 who also harbor Bmp4 mutations. This study demonstrates significant ECG and HRV responses to 24 hrs hyperoxia in mice, which highlights the need to further work on the genetic mechanisms associated with cardiac susceptibility to hyperoxia.
    Inhalation Toxicology 07/2013; · 1.89 Impact Factor
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    ABSTRACT: We generated a new Bmp2 conditional knock-out allele without a neo cassette and removed Bmp2 gene in osteoblasts (Bmp2-cKO(ob)) using the 3.6Col1a1-Cre transgenic model. Bones of Bmp2-cKO(ob) mice are thinner, with increased brittleness. Osteoblast activity is reduced as reflected in reduced bone formation rate, and failure to differentiate to a mature mineralizing stage. Bmp2 in osteoblasts also indirectly controls angiogenesis in the periosteum and bone marrow. VegfA production is reduced in Bmp2-cKO(ob) osteoblasts. Deletion of Bmp2 in osteoblasts also leads to defective mesenchymal stem cells (MSC), which correlates with the reduced microvascular bed in the periosteum and trabecular bones. Several marker genes of MSC (α-SMA, CD146 and Angiopoietin-1), in vitro CFU assays and deletion of the Bmp2 gene in vitro in α-SMA+ BMSC support our conclusions. Critical roles of the Bmp2 gene in osteoblasts and MSC are a vital link between bone formation, vascularization and mesenchymal stem cells.
    Journal of Cell Science 07/2013; · 5.33 Impact Factor
  • Yoshihiro Komatsu, Yuji Mishina
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    ABSTRACT: Establishment of vertebrate left-right asymmetry is a critical process for normal embryonic development. After the discovery of genes expressed asymmetrically along the left-right axis in chick embryos in the mid 1990s, the molecular mechanisms responsible for left-right patterning in vertebrate embryos have been studied extensively. In this review article, we discuss the mechanisms by which the initial symmetry along the left-right axis is broken in the mouse embryo. We focus on the role of primary cilia and molecular mechanisms of ciliogenesis at the node when symmetry is broken and left-right asymmetry is established. The node is considered a signaling center for early mouse embryonic development, and the results we review here have led to a better understanding of how the node functions and establishes left-right asymmetry.
    Cellular and Molecular Life Sciences CMLS 06/2013; · 5.86 Impact Factor
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    ABSTRACT: Sertoli cells provide nutritional and physical support to germ cells during spermatogenesis. Sox8 encodes a member of the high mobility group of transcription factors closely related to Sox9 and Sox10. Sertoli cells express SOX8 protein, and its elimination results in an age-dependent dysregulation of spermatogenesis, causing adult male infertility. Among the claudin genes with altered expression in the Sox8(-/-) testes, was claudin-3, which is required for the regulation and maintenance of the blood-testes barrier (BTB). Since the blood-testes barrier is critical in restricting small molecules in the luminal compartment of the seminiferous tubules, the aim of this study was to analyze the level of tight junction proteins (claudin-3, claudin-11, and occludin) and BTB permeability in Sox8(-/-) adult testes. The acetylation level of alpha-tubulin and microtubule organization was also evaluated, since microtubules are critical in microenvironment maintenance of the seminiferous epithelium. Western blot analysis shows that claudin-3 protein is decreased in Sox8(-/-) testes. Chromatin immunoprecipitation confirmed that SOX8 binds at the promoter region of claudin-3. Claudin-3 was localized to the Sertoli cell tight junctions of wild-type testes and significantly decreased in the Sox8(-/-) testes. The use of biotin tracers showed increased BTB permeability in the Sox8(-/-) adult testes. Electron microscopy analysis showed that microtubule structures are destabilized in the Sox8(-/-) testes. These results suggest that Sox8 is essential in Sertoli cells for germ cell differentiation, partly by controlling the microenvironment of the seminiferous epithelium.
    Biology of Reproduction 04/2013; · 3.45 Impact Factor
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    ABSTRACT: Constitutively activating mutations in receptor kinases recruit downstream effector pathways independently of upstream signaling, with consequences ranging from developmental syndromes to cancer. Classic fibrodysplasia ossificans progressiva (FOP) is a congenital syndrome resulting from highly conserved activating mutations of the glycine/serine-rich (GS-) regulatory domain of ACVR1 encoding BMP type I receptor ALK2, which lead to inappropriate signaling and heterotopic ossification of soft tissues. It is unclear if constitutively-active mutant ALK2 receptors (caALK2) can function independently of signaling complexes with type II receptors and ligands. We found that ablation of BmpRII and ActRIIa abrogated BMP ligand-mediated and caALK2-mediated signaling and transcription in cells, and disrupted caALK2-induced heterotopic ossification in mice. Signaling via GS-domain ALK2 mutants could be restored by the expression of either BMP type II receptor. The contribution of BMP type II receptors was independent of their ligand-binding or kinase function, but dependent upon an intact cytoplasmic domain. These data demonstrate that GS-domain ALK2 mutants act independently of upstream signaling, but may require non-enzymatic scaffolding function provided by type II receptors to form functional, apparently ligand-independent signaling complexes. These findings define the minimal requirements for signaling of GS-domain ALK2 mutants, with implications for the therapeutic targeting of their activity in disease.
    Molecular and Cellular Biology 04/2013; · 5.04 Impact Factor
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    ABSTRACT: While the importance of TGF-b superfamily signaling in craniofacial growth and patterning is well-established, the precise details of its signaling mechanisms are still poorly understood. This is in part because of the concentration of studies on the role of the Smad-dependent (so-called -canonical) signaling pathways relative to the Smad-independent ones in many biological processes. Here, we have addressed the role of Tak1 (Map3k7), one of the key mediators of Smad-independent (non-canonical) TGF-b superfamily signaling in craniofacial development by deleting Tak1 specifically in the neural crest lineage. Tak1-deficient mutants display a round skull, hypoplastic maxilla and mandible, and cleft palate resulting from a failure of palatal shelves to appropriately elevate and fuse. Our studies show that in neural crest-derived craniofacial ecto-mesenchymal cells Tak1 is not only required for TGF-b- and BMP-induced p38 Mapk activation, but also plays a role in agonist-induced C-terminal and linker region phosphorylation of the receptor-mediated R-Smads. Specifically, we demonstrate that the agonist-induced linker region phosphorylation of Smad2 at Thr220, which has been shown to be critical for full transcriptional activity of Smad2, is dependent on Tak1 activity, and that in palatal mesenchymal cells TGFbRI and Tak1 kinases mediate both overlapping and distinct TGF-b2-induced transcriptional responses. To summarize, our results suggest that in neural crest-derived ecto-mesenchymal cells, Tak1 provides a critical point of intersection in a complex dialogue between the canonical and non-canonical arms of TGF-b superfamily signaling required for normal craniofacial development.
    Journal of Biological Chemistry 04/2013; · 4.60 Impact Factor
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    ABSTRACT: Maintenance of body temperature is essential for the survival of homeotherms. Brown adipose tissue (BAT) is a specialized fat tissue that is dedicated to thermoregulation. Owing to its remarkable capacity to dissipate stored energy and its demonstrated presence in adult humans, BAT holds great promise for the treatment of obesity and metabolic syndrome. Rodent data suggest the existence of two types of brown fat cells: constitutive BAT (cBAT), which is of embryonic origin and anatomically located in the interscapular region of mice; and recruitable BAT (rBAT), which resides within white adipose tissue (WAT) and skeletal muscle, and has alternatively been called beige, brite or inducible BAT. Bone morphogenetic proteins (BMPs) regulate the formation and thermogenic activity of BAT. Here we use mouse models to provide evidence for a systemically active regulatory mechanism that controls whole-body BAT activity for thermoregulation and energy homeostasis. Genetic ablation of the type 1A BMP receptor (Bmpr1a) in brown adipogenic progenitor cells leads to a severe paucity of cBAT. This in turn increases sympathetic input to WAT, thereby promoting the formation of rBAT within white fat depots. This previously unknown compensatory mechanism, aimed at restoring total brown-fat-mediated thermogenic capacity in the body, is sufficient to maintain normal temperature homeostasis and resistance to diet-induced obesity. These data suggest an important physiological cross-talk between constitutive and recruitable brown fat cells. This sophisticated regulatory mechanism of body temperature may participate in the control of energy balance and metabolic disease.
    Nature 03/2013; · 42.35 Impact Factor
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    ABSTRACT: Specification of progenitors into the osteoblast lineage is an essential event for skeletogenesis. During endochondral ossification, cells in the perichondrium give rise to osteoblast precursors. Hedgehog (Hh) and bone morphogenetic protein (BMP) are suggested to regulate the commitment of these cells. However, properties of perichondrial cells and regulatory mechanisms of the specification process are still poorly understood. Here, we investigated the machineries by combining a novel organ culture system and single-cell expression analysis with mouse genetics and biochemical analyses. In a metatarsal organ culture reproducing bone collar formation, activation of BMP signaling enhanced the bone collar formation cooperatively with Hh input, while the signaling induced ectopic chondrocyte formation in the perichondrium without Hh input. Similar phenotypes were also observed in compound mutant mice, where signaling activities of Hh and BMP were genetically manipulated. Single-cell RT-qPCR analyses showed heterogeneity of perichondrial cells in terms of natural characteristics and responsiveness to Hh input. In vitro analyses revealed that Hh signaling suppressed BMP-induced chondrogenic differentiation; Gli1 inhibited the expression of Sox5, Sox6, and Sox9 as well as transactivation by Sox9. Indeed, ectopic expression of chondrocyte maker genes were observed in the perichondrium of metatarsals in Gli1-/- fetuses, and the phenotype was more severe in Gli1-/-;Gli2-/- newborns. These data suggest that Hh-Gli activators alter the function of BMP to specify perichondrial cells into osteoblasts; the timing of Hh input and its target populations are critical for BMP function.
    Journal of Biological Chemistry 02/2013; · 4.60 Impact Factor

Publication Stats

9k Citations
1,098.76 Total Impact Points

Institutions

  • 2014
    • Kinki University
      Ōsaka, Ōsaka, Japan
  • 2013–2014
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • University of North Carolina at Charlotte
      • Department of Kinesiology
      Charlotte, NC, United States
  • 2008–2014
    • University of Michigan
      • • Department of Biologic and Materials Sciences
      • • School of Dentistry
      Ann Arbor, Michigan, United States
    • National Eye Institute
      Maryland, United States
    • University of Houston
      Houston, Texas, United States
  • 2008–2013
    • Baylor College of Dentistry
      • Department of Biomedical Sciences
      Dallas, Texas, United States
  • 2012
    • Nagoya University
      • Graduate School of Science
      Nagoya-shi, Aichi-ken, Japan
    • Institute of Molecular Biology
      Mayence, Rheinland-Pfalz, Germany
    • Keio University
      • Center for Integrated Medical Research
      Tokyo, Tokyo-to, Japan
  • 2008–2012
    • North Carolina State University
      • Department of Environmental and Molecular Toxicology
      Raleigh, NC, United States
  • 2004–2012
    • National Institutes of Health
      • Branch of Reproductive and Developmental Toxicology
      Maryland, United States
  • 2002–2012
    • National Institute of Environmental Health Sciences
      • Laboratory of Reproductive and Developmental Toxicology (LRDT)
      Durham, North Carolina, United States
  • 2011
    • Texas Scottish Rite Hospital for Children
      Texas City, Texas, United States
  • 2006–2008
    • Research Triangle Park Laboratories, Inc.
      Raleigh, North Carolina, United States
  • 1995–2006
    • University of Texas MD Anderson Cancer Center
      • Human and Molecular Genetics
      Houston, TX, United States
  • 2004–2005
    • University of Missouri - Kansas City
      • Department of Oral Biology
      Kansas City, MO, United States
  • 1995–2003
    • Baylor College of Medicine
      • Department of Molecular & Human Genetics
      Houston, Texas, United States
  • 2000
    • Monash University (Australia)
      Melbourne, Victoria, Australia