Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling

Lenton, Kelly A.; James, Aaron W.; Manu, Alina; Brugmann, Samantha A.; Birker, Daniel; Nelson, Emily R.; Leucht, Philipp; Helms, Jill A.; Longaker, Michael T.

doi:10.1002/dvg.20768

Cited by 86 publications

(110 citation statements)

References 52 publications

(56 reference statements)

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“…In one study, Ihh gain-and loss-offunction experiments in chick and mouse suggest that Hh signaling blocks the transition of pre-osteoblasts to osteoblasts (Abzhanov et al, 2007). An opposing study reported an overall decrease in markers of osteoblast differentiation in the calvaria of Ihh-null mice, suggesting that Hh signaling is pro-osteogenic (Lenton et al, 2011). As we did not detect any changes in osteoblast stage markers in ihha mutants, our data more closely fit the proosteogenic model put forth by Lenton et al, as their observed reduction in osteoblast markers might reflect differences in the rate of progenitor proliferation.…”

Section: Research Articlesupporting

confidence: 87%

“…Development of the bone lineage involves the sequential transition of cells through discrete stages (Bruder and Caplan, 1989;Bruder and Caplan, 1990;Li et al, 2009), and Ihh function has previously been associated with regulating osteoblast differentiation during dermal bone development (Abzhanov et al, 2007;Lenton et al, 2011). As a change to this ordered progression could result in the observed phenotypes, we looked at bone lineage markers at 3 dpf and 5 dpf.…”

Section: Ordered Progression Through Stages Of Osteoblast Differentiamentioning

confidence: 99%

“…A model for how ihha regulates modular morphogenesis Previous work has revealed conflicting mechanisms by which Hh signaling may regulate dermal bone development (Abzhanov et al, 2007;Lenton et al, 2011). In one study, Ihh gain-and loss-offunction experiments in chick and mouse suggest that Hh signaling blocks the transition of pre-osteoblasts to osteoblasts (Abzhanov et al, 2007).…”

Section: Research Articlementioning

confidence: 99%

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Hedgehog-dependent proliferation drives modular growth during morphogenesis of a dermal bone

2012

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SUMMARYIn the developing skeleton, dermal bone morphogenesis includes the balanced proliferation, recruitment and differentiation of osteoblast precursors, yet how bones acquire unique morphologies is unknown. We show that Hedgehog (Hh) signaling mediates bone shaping during early morphogenesis of the opercle (Op), a well characterized dermal bone of the zebrafish craniofacial skeleton. ihha is specifically expressed in a local population of active osteoblasts along the principal growing edge of the bone. Mutational studies show that Hh signaling by this osteoblast population is both necessary and sufficient for full recruitment of pre-osteoblasts into the signaling population. Loss of ihha function results in locally reduced proliferation of pre-osteoblasts and consequent reductions in recruitment into the osteoblast pool, reduced bone edge length and reduced outgrowth. Conversely, hyperactive Hh signaling in ptch1 mutants causes opposite defects in proliferation and growth. Time-lapse microscopy of early Op morphogenesis using transgenically labeled osteoblasts demonstrates that ihha-dependent bone development is not only region specific, but also begins exactly at the onset of a second phase of morphogenesis, when the early bone begins to reshape into a more complex form. These features strongly support a hypothesis that dermal bone development is modular, with different gene sets functioning at specific times and locations to pattern growth. The Hh-dependent module is not limited to this second phase of bone growth: during later larval development, the Op is fused along the dysmorphic edge to adjacent dermal bones. Hence, patterning within a module may include adjacent regions of functionally related bones and might require that signaling pathways function over an extended period of development.

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Section: Research Articlesupporting

confidence: 87%

Section: Ordered Progression Through Stages Of Osteoblast Differentiamentioning

confidence: 99%

Section: Research Articlementioning

confidence: 99%

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Hedgehog-dependent proliferation drives modular growth during morphogenesis of a dermal bone

2012

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“…Interestingly, the recent identification of genetic lesions in RAB23 and IHH in humans has implicated the involvement of Hh signaling in craniosynostosis pathophysiology (Jenkins et al, 2007;Klopocki et al, 2011). Although correlative studies in mouse have suggested a functional role for Ihh at late stages of suture development (Lenton et al, 2011), our lineage-tracing strategies provide the opportunity for investigating whether Hh responsiveness in primordial sutural and osteogenic precursors is crucial for even earlier processes pertaining to cell migration, specification and patterning (E7.5-8.5).…”

Section: Discussionmentioning

confidence: 99%

Regulation of cranial morphogenesis and cell fate at the neural crest-mesoderm boundary by engrailed 1

et al. 2012

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SUMMARYThe characterization of mesenchymal progenitors is central to understanding development, postnatal pathology and evolutionary adaptability. The precise identity of the mesenchymal precursors that generate the coronal suture, an important structural boundary in mammalian skull development, remains unclear. We show in mouse that coronal suture progenitors originate from hedgehog-responsive cephalic paraxial mesoderm (Mes) cells, which migrate rapidly to a supraorbital domain and establish a unidirectional lineage boundary with neural crest (NeuC) mesenchyme. Lineage tracing reveals clonal and stereotypical expansion of supraorbital mesenchymal cells to form the coronal suture between E11.0 and E13.5. We identify engrailed 1 (En1) as a necessary regulator of cell movement and NeuC/Mes lineage boundary positioning during coronal suture formation. In addition, we provide genetic evidence that En1 functions upstream of fibroblast growth factor receptor 2 (Fgfr2) in regulating early calvarial osteogenic differentiation, and postulate that it plays an additional role in precluding premature osteogenic conversion of the sutural mesenchyme.

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“…Furthermore, ihha is robustly expressed in blastemal Obs during regeneration (Avaron et al, 2006). Therefore, Ihha rather than Shha could account for ptch2 induction in regenerating Obs and in the direct control of osteoblast growth and/or differentiation in a manner recapitulating the proposed developmental roles of Ihh (Abzhanov et al, 2007;Huycke et al, 2012;Lenton et al, 2011;Long, 2012).…”

Section: Introductionmentioning

confidence: 98%

Shh promotes direct interactions between epidermal cells and osteoblast progenitors to shape regenerated zebrafish bone

et al. 2017

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Zebrafish innately regenerate amputated fins by mechanisms that expand and precisely position injury-induced progenitor cells to re-form tissue of the original size and pattern. For example, cell signaling networks direct osteoblast progenitors (pObs) to rebuild thin cylindrical bony rays with a stereotypical branched morphology. Hedgehog/ Smoothened (Hh/Smo) signaling has been variably proposed to stimulate overall fin regenerative outgrowth or promote ray branching. Using a photoconvertible patched2 reporter, we resolve active Hh/Smo output to a narrow distal regenerate zone comprising pObs and adjacent motile basal epidermal cells. This Hh/Smo activity is driven by epidermal Sonic hedgehog a (Shha) rather than Ob-derived Indian hedgehog a (Ihha), which nevertheless functions atypically to support bone maturation. Using BMS-833923, a uniquely effective Smo inhibitor, and high-resolution imaging, we show that Shha/Smo is functionally dedicated to ray branching during fin regeneration. Hh/ Smo activation enables transiently divided clusters of Shha-expressing epidermis to escort pObs into similarly split groups. This co-movement likely depends on epidermal cellular protrusions that directly contact pObs only where an otherwise occluding basement membrane remains incompletely assembled. Progressively separated pObs pools then continue regenerating independently to collectively reform a now branched skeletal structure.

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Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling

Cited by 86 publications

References 52 publications

Hedgehog-dependent proliferation drives modular growth during morphogenesis of a dermal bone

Hedgehog-dependent proliferation drives modular growth during morphogenesis of a dermal bone

Regulation of cranial morphogenesis and cell fate at the neural crest-mesoderm boundary by engrailed 1

Shh promotes direct interactions between epidermal cells and osteoblast progenitors to shape regenerated zebrafish bone

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