I only have eye for ewe: the discovery of cyclopamine and development of Hedgehog pathway-targeting drugs

Chen, James

doi:10.1039/c5np00153f

Cited by 63 publications

(41 citation statements)

References 45 publications

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“…In vitro imaging revealed that this protein was more abundant towards the centre compared with the peripheral layers (Figure L–N). These cells were then cultured in medium containing a hedgehog inhibitor, cyclopamine, which is known to induce severe bone malformations (Chen, ). Compared to the vehicle treated samples (Figure O), lower concentrations (10 and 20 μ m ) delayed self‐aggregation (data not shown); a higher concentration (100 μ m ) prevented it entirely (Figure P).…”

Section: Resultsmentioning

confidence: 99%

Limb derived cells as a paradigm for engineering self‐assembling skeletal tissues

Fernando

Papantoniou

Mendes

et al. 2017

J Tissue Eng Regen Med

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Mimicking developmental events has been proposed as a strategy to engineer tissue constructs for regenerative medicine. However, this approach has not yet been investigated for skeletal tissues. Here, it is demonstrated that ectopic implantation of day-14.5 mouse embryonic long bone anlagen, dissociated into single cells and randomly incorporated in a bioengineered construct, gives rise to epiphyseal growth plate-like structures, bone and marrow, which share many morphological and molecular similarities to epiphyseal units that form after transplanting intact long bone anlage, demonstrating substantial robustness and autonomy of complex tissue self-assembly and the overall organogenesis process. In vitro studies confirm the self-aggregation and patterning capacity of anlage cells and demonstrate that the model can be used to evaluate the effects of large and small molecules on biological behaviour. These results reveal the preservation of self-organizing and self-patterning capacity of anlage cells even when disconnected from their developmental niche and subjected to system perturbations such as cellular dissociation. These inherent features make long bone anlage cells attractive as a model system for tissue engineering technologies aimed at creating constructs that have the potential to self-assemble and self-pattern complex architectural structures.

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Section: Resultsmentioning

confidence: 99%

Limb derived cells as a paradigm for engineering self‐assembling skeletal tissues

Fernando

Papantoniou

Mendes

et al. 2017

J Tissue Eng Regen Med

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“…Importantly, vismodegib is part of a larger class of compounds that inhibit Hh signaling by binding to the transmembrane protein Smoothened (Robarge et al, 2009; Chen et al, 2002; Keeler, 1975; Chen, 2016). With both synthetic and natural small molecules, this group includes more than 20 compounds and continues to grow, with increasing attention focused on the biological effects of Hh-pathway inhibition.…”

Section: Discussionmentioning

confidence: 99%

Gli2 gene-environment interactions contribute to the etiological complexity of holoprosencephaly: evidence from a mouse model

Heyne

Everson

Ansen-Wilson

et al. 2016

Disease Models &Amp; Mechanisms

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Holoprosencephaly (HPE) is a common and severe human developmental abnormality marked by malformations of the forebrain and face. Although several genetic mutations have been linked to HPE, phenotypic outcomes range dramatically, and most cases cannot be attributed to a specific cause. Gene-environment interaction has been invoked as a premise to explain the etiological complexity of HPE, but identification of interacting factors has been extremely limited. Here, we demonstrate that mutations in Gli2, which encodes a Hedgehog pathway transcription factor, can cause or predispose to HPE depending upon gene dosage. On the C57BL/6J background, homozygous GLI2 loss of function results in the characteristic brain and facial features seen in severe human HPE, including midfacial hypoplasia, hypotelorism and medial forebrain deficiency with loss of ventral neurospecification. Although normally indistinguishable from wild-type littermates, we demonstrate that mice with single-allele Gli2 mutations exhibit increased penetrance and severity of HPE in response to low-dose teratogen exposure. This genetic predisposition is associated with a Gli2 dosage-dependent attenuation of Hedgehog ligand responsiveness at the cellular level. In addition to revealing a causative role for GLI2 in HPE genesis, these studies demonstrate a mechanism by which normally silent genetic and environmental factors can interact to produce severe outcomes. Taken together, these findings provide a framework for the understanding of the extreme phenotypic variability observed in humans carrying GLI2 mutations and a paradigm for reducing the incidence of this morbid birth defect.

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“…The first such molecule discovered is the naturally occurring teratogen and SMO antagonist, cyclopamine (Chen, 2016). Human exposure to naturally occurring or synthetic SMO inhibitors may therefore be a risk factor for HPE.…”

Section: Gene-environment Interactions In Hpementioning

confidence: 99%

Modeling the complex etiology of holoprosencephaly in mice

Hong

Krauss

2018

American J of Med Genetics Pt C

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Holoprosencephaly (HPE) is a common developmental defect caused by failure to define the midline of the forebrain and/or midface. HPE is associated with heterozygous mutations in Nodal and Sonic hedgehog (SHH) pathway components, but clinical presentation is highly variable, and many mutation carriers are unaffected. It is therefore thought that such mutations interact with more common modifiers, genetic and/or environmental, to produce severe patterning defects. Modifiers are difficult to identify, as their effects are context-dependent and occur within the complex genetic and environmental landscapes that characterize human populations. This has made a full understanding of HPE etiology challenging. We discuss here the use of mice, a genetically tractable model sensitive to teratogens, as a system to address this challenge. Mice carrying mutations in human HPE genes often display wide variations in phenotypic penetrance and expressivity when placed on different genetic backgrounds, demonstrating the existence of silent HPE modifier genes. Studies with mouse lines carrying SHH pathway mutations on appropriate genetic backgrounds have led to identification of both genetic and environmental modifiers that synergize with the mutations to produce a spectrum of HPE phenotypes. These models favor a scenario in which multiple modifying influences-both genetic and environmental, sensitizing and protective-interact with bona fide HPE mutations to grade phenotypic outcomes. Despite the complex interplay of HPE risk factors, mouse models have helped establish some clear concepts in HPE etiology. A combination of mouse and human cohort studies should improve our understanding of this fascinating and medically important issue.

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I only have eye for ewe: the discovery of cyclopamine and development of Hedgehog pathway-targeting drugs

Cited by 63 publications

References 45 publications

Limb derived cells as a paradigm for engineering self‐assembling skeletal tissues

Limb derived cells as a paradigm for engineering self‐assembling skeletal tissues

Gli2 gene-environment interactions contribute to the etiological complexity of holoprosencephaly: evidence from a mouse model

Modeling the complex etiology of holoprosencephaly in mice

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