Shox2-deficiency leads to dysplasia and ankylosis of the temporomandibular joint in mice

Gu, Shaohua; Wei, Na; Yu, Ling; Fei, Jian

doi:10.1016/j.mod.2008.04.003

Cited by 64 publications

(103 citation statements)

References 47 publications

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“…In mice, ablation of Shox2 causes embryonic lethality at midgestation due to cardiac and vascular defects (11). Studies of Shox2-null and conditional knockout mice have shown an indispensable role of Shox2 in the formation of the proximal portion of the limb skeleton and synovial joints (12,13). The shortened limbs observed in Turner syndrome may be related to loss of SHOX (14,15).…”

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confidence: 99%

Shox2 is a molecular determinant of depot-specific adipocyte function

Lee

Yamamoto

Boucher

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Visceral and s.c. fat exhibit different intrinsic properties, including rates of lipolysis, and are associated with differential risk for the development of type 2 diabetes. These effects are in part related to cell autonomous differences in gene expression. In the present study, we show that expression of Shox2 (Short stature homeobox 2) is higher in s.c. than visceral fat in both rodents and humans and that levels are further increased in humans with visceral obesity. Fat-specific disruption of Shox2 in male mice results in protection from high fat diet-induced obesity, with a preferential loss of s.c. fat. The reduced adipocyte size is secondary to a twofold increase in the expression of β3 adrenergic receptor ( Adrb3 ) at both the mRNA and protein level and a parallel increase in lipolytic rate. These effects are mimicked by knockdown of Shox2 in C3H10T1/2 cells. Conversely, overexpression of Shox2 leads to a repression of Adrb3 expression and decrease lipolytic rate. Shox2 does not affect differentiation but directly interacts with CCAAT/enhancer binding protein alpha and attenuates its transcriptional activity of the Adrb3 promoter. Thus, Shox2 can regulate the expression of Adrb3 and control the rate of lipolysis and, in this way, exerts control of the phenotypic differences between visceral and s.c. adipocytes.

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mentioning

confidence: 99%

Shox2 is a molecular determinant of depot-specific adipocyte function

Lee

Yamamoto

Boucher

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…1, upper right) (18,19). One key gene previously noted to be expressed during and function within the growth plate of the condylar cartilage is Indian hedgehog (Ihh) (20)(21)(22). Ihh has been studied extensively during endochondral ossification of the long bones, where it plays several distinct roles.…”

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confidence: 99%

Temporomandibular joint formation requires two distinct hedgehog-dependent steps

Purcell

Joo

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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We conducted a genetic analysis of the developing temporo-mandibular or temporomandi-bular joint (TMJ), a highly specialized synovial joint that permits movement and function of the mammalian jaw. First, we used laser capture microdissection to perform a genome-wide expression analysis of each of its developing components. The expression patterns of genes identified in this screen were examined in the TMJ and compared with those of other synovial joints, including the shoulder and the hip joints. Striking differences were noted, indicating that the TMJ forms via a distinct molecular program. Several components of the hedgehog ( Hh ) signaling pathway are among the genes identified in the screen, including Gli2 , which is expressed specifically in the condyle and in the disk of the developing TMJ. We found that mice deficient in Gli2 display aberrant TMJ development such that the condyle loses its growth-plate-like cellular organization and no disk is formed. In addition, we used a conditional strategy to remove Smo , a positive effector of the Hh signaling pathway, from chondrocyte progenitors. This cell autonomous loss of Hh signaling allows for disk formation, but the resulting structure fails to separate from the condyle. Thus, these experiments establish that Hh signaling acts at two distinct steps in disk morphogenesis, condyle initiation, and disk–condyle separation and provide a molecular framework for future studies of the TMJ.

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“…Most obviously, mouse embryos nullizygous for Shox2 die between E11.5 and E17.5 due to aberrant formation of the sinoatrial node (Blaschke et al, 2007;Espinoza-Lewis et al, 2009;Yu et al, 2007). Shox2 mutants also exhibit a unique incomplete clefting phenotype of the future hard palate (Yu et al, 2005), as well as defects in temporomandibular joint formation (Gu et al, 2008) and in the differentiation of Ntrk2-positive dorsal root ganglion mechanosensory neurons (Scott et al, 2011). Finally, loss of Shox2 function in embryonic limb mesenchyme causes significant neural and muscular patterning defects in the forelimb stylopod (Vickerman et al, 2011), in addition to severe rhizomelia (Cobb et al, 2006;Yu et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Shox2regulates progression through chondrogenesis in the mouse proximal limb

Bobick

Cobb

2012

Journal of Cell Science

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SummaryIn humans, loss of SHOX gene function is responsible for the mesomelic short stature characteristic of Turner syndrome, Leri-Weill dyschondrosteosis, and Langer dysplasia. In a mouse model of SHOX deficiency, Prrx1-Cre-driven limb-specific deletion of the paralogous gene Shox2 results in severe rhizomelia. In this study, we show that Col2a1-Cre-driven deletion of Shox2 in developing chondrocytes also results in shortening of the stylopodial skeleton (i.e. humerus, femur) and that this rhizomelia is due to precocious chondrocyte maturation and hypertrophy. We demonstrate, using the micromass culture model system, that increased BMP activity triggers accelerated maturation and hypertrophy in Col2a1-Cre Shox2 mutant chondrocytes and we confirm in vivo that elevated transcript levels and expanded expression domains of Bmp2 and 4 are associated with premature formation of the hypertrophic zone in mutant humeri. In micromass cultures of Prrx1-Cre Shox2 mutant limb cells, we find that Shox2 deletion in undifferentiated mesenchymal cells results in increased BMP activity that enhances early chondrogenesis, but is insufficient to provoke chondrocyte maturation and hypertrophy. Similarly, shRNA-mediated Shox2 knockdown in multipotent C3H10T1/2 cells and primary mouse bone marrow mesenchymal stem cells results in spontaneous chondrogenesis in the absence of chondrostimulation, but again fails to induce progression through the later stages of chondrogenic differentiation. Importantly, exogenous BMP supplementation can overcome the block to maturation and hypertrophy caused by Shox2 depletion prior to overt chondrogenesis. Thus, we provide evidence that Shox2 regulates progression through chondrogenesis at two distinct stages -the onset of early differentiation and the transition to maturation and hypertrophy.

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Shox2-deficiency leads to dysplasia and ankylosis of the temporomandibular joint in mice

Cited by 64 publications

References 47 publications

Shox2 is a molecular determinant of depot-specific adipocyte function

Shox2 is a molecular determinant of depot-specific adipocyte function

Temporomandibular joint formation requires two distinct hedgehog-dependent steps

Shox2regulates progression through chondrogenesis in the mouse proximal limb

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