Gli3 acts as a repressor downstream of Ihh in regulating two distinct steps of chondrocyte differentiation

Koziel, Lydia; Wuelling, Manuela; Schneider, Sabine; Vortkamp, Andrea

doi:10.1242/dev.02097

Cited by 135 publications

(121 citation statements)

References 42 publications

(42 reference statements)

Supporting

Mentioning

113

Contrasting

Order By: Relevance

“…This observation is consistent with our previous finding that Ihh and Igf control the linear growth of the skeleton largely independently (29). In addition, previous studies have demonstrated that Ihh controls cartilage development chiefly through derepression of Gli3, but induces osteoblastogenesis via both Gli3 derepression and Gli2 activation (16,41,42). Here, we show that Igf signaling stabilizes full-length Gli2 but not Gli3.…”

Section: Discussionsupporting

confidence: 93%

Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation

Shi¹,

Chen²,

Karner³

et al. 2015

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

View full text Add to dashboard Cite

Hedgehog (Hh) signaling is essential for osteoblast differentiation in the endochondral skeleton during embryogenesis. However, the molecular mechanism underlying the osteoblastogenic role of Hh is not completely understood. Here, we report that Hh markedly induces the expression of insulin-like growth factor 2 (Igf2) that activates the mTORC2-Akt signaling cascade during osteoblast differentiation. Igf2-Akt signaling, in turn, stabilizes full-length Gli2 through Serine 230, thus enhancing the output of transcriptional activation by Hh. Importantly, genetic deletion of the Igf signaling receptor Igf1r specifically in Hh-responding cells diminishes bone formation in the mouse embryo. Thus, Hh engages Igf signaling in a positive feedback mechanism to activate the osteogenic program.

show abstract

Section: Discussionsupporting

confidence: 93%

Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation

Shi¹,

Chen²,

Karner³

et al. 2015

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

View full text Add to dashboard Cite

show abstract

“…Previous studies showed that growth plate defects in Ihh Ϫ/Ϫ long bones are partially corrected in double Ihh Ϫ/Ϫ /Gli3 Ϫ/Ϫ mutants (Hilton et al, 2005;Koziel et al, 2005). Our data support those observations, as we observe similar trends of recovery in double mutant condyles, including (1) restoration of proliferation and PTHrP and Sox9 expression in the polymorphic layer and (2) improved expression of PTHrP-R and collagen X and more normal maturation rates in growth plate.…”

Section: Ihhsupporting

confidence: 91%

“…Subsequent studies on Ihh Ϫ/Ϫ mouse embryos showed that Ihh regulates chondrocyte proliferation and rates of chondrocyte maturation in cooperation with periarticular cell-derived parathyroid hormone-related protein (PTHrP; Lanske et al, 1996;St-Jacques et al, 1999;Long et al, 2001). Unexpectedly, those studies revealed also that the mutant embryos displayed severe defects in limb synovial joints particularly in the autopods, suggesting that defects in growth plate have repercussions on joint formation (St-Jacques et al, 1999 (Hilton et al, 2005;Koziel et al, 2005).…”

Section: Introductionmentioning

confidence: 94%

See 1 more Smart Citation

Temporomandibular joint formation and condyle growth require Indian hedgehog signaling

Shibukawa¹,

Young²,

Wu³

et al. 2006

Developmental Dynamics

131

174

View full text Add to dashboard Cite

The temporomandibular joint (TMJ) is essential for jaw function, but the mechanisms regulating its development remain poorly understood. Because Indian hedgehog (Ihh) regulates trunk and limb skeletogenesis, we studied its possible roles in TMJ development. In wild-type mouse embryos, Ihh expression was already strong in condylar cartilage by embryonic day (E) 15.5, and expression of Ihh receptors and effector genes (Gli1, Gli2, Gli3, and PTHrP) indicated that Ihh range of action normally reached apical condylar tissue layers, including polymorphic chondroprogenitor layer and articular disc primordia. In Ihh ؊/؊ embryos, TMJ development was severely compromised. Condylar cartilage growth, polymorphic cell proliferation, and PTHrP expression were all inhibited, and growth plate organization and chondrocyte gene expression patterns were abnormal. These severe defects were partially corrected in double Ihh ؊/؊ /Gli3؊/؊ mutants, signifying that Ihh action is normally modulated and delimited by Gli3 and Gli3 R in particular. Both single and double mutants, however, failed to form an articular disc primordium, normally appreciable as an independent condensation between condylar apex and neighboring developing temporal bone in wild-type. This failure persisted at later stages, leading to complete absence of a normal functional disc and lubricin-expressing joint cavities. In summary, Ihh is very important for TMJ development, where it appears to regulate growth and elongation events, condylar cartilage phenotype, and chondroprogenitor cell function. Absence of articular disc and joint cavities in single and double mutants points to irreplaceable Ihh roles in formation of those critical TMJ components. Developmental Dynamics 236:426 -434, 2007.

show abstract

“…It is important here to note that the contribution of signaling systems to particular skeletal structures varies (Koziel et al, 2005), which provides a mechanism by which the diversity of bones in all shapes and sizes can be achieved. Secondly, it is evident that the molecules that regulate chondrocyte differentiation are also involved in prior phases of skeletal development.…”

Section: Local Control Of Bone Shape During Embryogenesis and Growthmentioning

confidence: 99%

Molecular basis for skeletal variation: insights from developmental genetic studies in mice

Kappen

Neubüser

Balling

et al. 2007

Birth Defects Research Pt B

View full text Add to dashboard Cite

Skeletal variations are common in humans, and potentially are caused by genetic as well as environmental factors. We here review molecular principles in skeletal development to develop a knowledge base of possible alterations that could explain variations in skeletal element number, shape or size. Environmental agents that induce variations, such as teratogens, likely interact with the molecular pathways that regulate skeletal development. Birth Defects Res (Part B), 80:425–450, 2007. © 2007 Wiley‐Liss, Inc.

show abstract

Gli3 acts as a repressor downstream of Ihh in regulating two distinct steps of chondrocyte differentiation

Cited by 135 publications

References 42 publications

Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation

Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation

Temporomandibular joint formation and condyle growth require Indian hedgehog signaling

Molecular basis for skeletal variation: insights from developmental genetic studies in mice

Contact Info

Product

Resources

About