Generation of <i>Evc2/Limbin</i> global and conditional <scp>KO</scp> mice and its roles during mineralized tissue formation

Zhang, Honghao; Takeda, Hitoshi; Tsuji, Takehito; Kamiya, Nobuhiro; Rajderkar, Sudha; Louie, Ke’ale W.; Collier, Crystal; Scott, Greig; Ray, Manas K.; Mochida, Yoshiyuki; Kaartinen, Vesa; Kunieda, Tetsuo; Mishina, Yuji

doi:10.1002/dvg.22879

Cited by 27 publications

(65 citation statements)

References 34 publications

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“…The same group also demonstrated compromised bone collar formation in Evc −/− mice in the C57BL/6 homogenous background but showed that both proliferation and differentiation of chondrocytes are compromised in mutant mice (Pacheco et al 2012). EVC and EVC2 are mutually required for their ciliary localization and loss of Evc2/Limbin results in similar skeletal phenotypes found in Evc −/− mice (Caparrós-Martín et al 2013;Zhang et al 2015).…”

Section: Primary Ciliamentioning

confidence: 82%

Developmental Regulation of the Growth Plate and Cranial Synchondrosis

Wei

Mishina

et al. 2016

J Dent Res

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Long bones and the cranial base are both formed through endochondral ossification. Elongation of long bones is primarily through the growth plate, which is a cartilaginous structure at the end of long bones made up of chondrocytes. Growth plate chondrocytes are organized in columns along the longitudinal axis of bone growth. The cranial base is the growth center of the neurocranium. Synchondroses, consisting of mirror-image growth plates, are critical for cranial base elongation and development. Over the last decade, considerable progress has been made in determining the roles of the parathyroid hormone-related protein, Indian hedgehog, fibroblast growth factor, bone morphogenetic protein, and Wnt signaling pathways in various aspects of skeletal development. Furthermore, recent evidence indicates the important role of the primary cilia signaling pathway in bone elongation. Here, we review the development of the growth plate and cranial synchondrosis and the regulation by the above-mentioned signaling pathways, highlighting the similarities and differences between these 2 structures.

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Section: Primary Ciliamentioning

confidence: 82%

Developmental Regulation of the Growth Plate and Cranial Synchondrosis

Wei

Mishina

et al. 2016

J Dent Res

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“…Upon induction of Hedgehog signaling, the EVC/EVC2 complex interacts with SMO at the base of cilium, which affects GLI2 accumulation in the ciliary tips [21, 23]. Consistent with in vitro mechanistic studies, diminished Hedgehog signaling was observed in the growth plates of mice lacking either Evc or Evc2 [23, 26, 27]. Since the Hedgehog-PTHrP loop has a central role in regulating chondrocyte proliferation and maturation, thereby determining the length of the appendicular skeleton, disrupted Hedgehog signaling in the growth plate is the speculated reason for dwarfism in the EvC syndrome [21, 23].…”

Section: Introductionmentioning

confidence: 95%

“…This discrepancy between the function of EVC/EVC2 in transducing Hedgehog signaling and phenotypic observations in Evc or Evc2 mutant mice prompted us to ask to what extent does the loss of function of Evc/Evc2 reduce Hedgehog signaling, and why does Evc/Evc2 loss of function specifically impact limb development. To answer these questions, we investigated Hedgehog signaling and FGF signaling levels during defective endochondral ossification in Evc2 mutant mouse lines [27]. We demonstrate that a nonsense mutation in Evc2 that mimics mutations seen in EvC patients, leads to compromised but not abrogated Hedgehog signaling.…”

Section: Introductionmentioning

confidence: 99%

Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice

et al. 2016

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Ellis-van Creveld (EvC) syndrome is a skeletal dysplasia, characterized by short limbs, postaxial polydactyly, and dental abnormalities. EvC syndrome is also categorized as a ciliopathy because of ciliary localization of proteins encoded by the two causative genes, EVC and EVC2 (aka LIMBIN). While recent studies demonstrated important roles for EVC/EVC2 in Hedgehog signaling, there is still little known about the pathophysiological mechanisms underlying the skeletal dysplasia features of EvC patients, and in particular why limb development is affected, but not other aspects of organogenesis that also require Hedgehog signaling. In this report, we comprehensively analyze limb skeletogenesis in Evc2 mutant mice and in cell and tissue cultures derived from these mice. Both in vivo and in vitro data demonstrate elevated Fibroblast Growth Factor (FGF) signaling in Evc2 mutant growth plates, in addition to compromised but not abrogated Hedgehog-PTHrP feedback loop. Elevation of FGF signaling, mainly due to increased Fgf18 expression upon inactivation of Evc2 in the perichondrium, critically contributes to the pathogenesis of limb dwarfism. The limb dwarfism phenotype is partially rescued by inactivation of one allele of Fgf18 in the Evc2 mutant mice. Taken together, our data uncover a novel pathogenic mechanism to understand limb dwarfism in patients with Ellis-van Creveld syndrome.

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“…Schema of main compartments of the primary cilium and gene product localization with association to dental phenotype. Beales et al 1999 Waters andBeales 2011 (continued) less severe phenotypes in the incisors and molar teeth (Zhang et al 2015). These data suggest that the primary cilia residing in the neural crest-derived mesenchyme are necessary for normal mineralization of the tooth.…”

Section: Ciliopathy Syndromes With Dental Phenotypementioning

confidence: 90%

Role of Primary Cilia in Odontogenesis

et al. 2017

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Primary cilium is a solitary organelle that emanates from the surface of most postmitotic mammalian cells and serves as a sensory organelle, transmitting the mechanical and chemical cues to the cell. Primary cilia are key coordinators of various signaling pathways during development and maintenance of tissue homeostasis. The emerging evidence implicates primary cilia function in tooth development. Primary cilia are located in the dental epithelium and mesenchyme at early stages of tooth development and later during cell differentiation and production of hard tissues. The cilia are present when interactions between both the epithelium and mesenchyme are required for normal morphogenesis. As the primary cilium coordinates several signaling pathways essential for odontogenesis, ciliary defects can interrupt the latter process. Genetic or experimental alterations of cilia function lead to various developmental defects, including supernumerary or missing teeth, enamel and dentin hypoplasia, or teeth crowding. Moreover, dental phenotypes are observed in ciliopathies, including Bardet-Biedl syndrome, Ellis-van Creveld syndrome, Weyers acrofacial dysostosis, cranioectodermal dysplasia, and oral-facial-digital syndrome, altogether demonstrating that primary cilia play a critical role in regulation of both the early odontogenesis and later differentiation of hard tissue-producing cells. Here, we summarize the current evidence for the localization of primary cilia in dental tissues and the impact of disrupted cilia signaling on tooth development in ciliopathies.

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Generation of Evc2/Limbin global and conditional KO mice and its roles during mineralized tissue formation

Cited by 27 publications

References 34 publications

Developmental Regulation of the Growth Plate and Cranial Synchondrosis

Developmental Regulation of the Growth Plate and Cranial Synchondrosis

Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice

Role of Primary Cilia in Odontogenesis

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