Sonic hedgehog-expressing cells in the developing limb measure time by an intrinsic cell cycle clock

Chinnaiya, Kavitha; Tickle, Cheryll; Towers, Matthew

doi:10.1038/ncomms5230

Cited by 37 publications

(71 citation statements)

References 26 publications

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“…This is similar to what we found previously with the cells of the polarizing region (Chinnaiya et al, 2014). Thus, it is the developmental stage of the distal progenitors rather than the length of time for which they developed, that limits their ability to reset their cell cycle program in an early environment.…”

Section: Hh20 Wings With Hh27 Grafts Have a Normal Aersupporting

confidence: 76%

Intrinsic properties of limb bud cells can be differentially reset

et al. 2017

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An intrinsic timing mechanism specifies the positional values of the zeugopod (i.e. radius/ulna) and then autopod (i.e. wrist/digits) segments during limb development. Here, we have addressed whether this timing mechanism ensures that patterning events occur only once by grafting GFP-expressing autopod progenitor cells to the earlier host signalling environment of zeugopod progenitor cells. We show by detecting Hoxa13 expression that early and late autopod progenitors fated for the wrist and phalanges, respectively, both contribute to the entire host autopod, indicating that the autopod positional value is irreversibly determined. We provide evidence that Hoxa13 provides an autopod-specific positional value that correctly allocates cells into the autopod, most likely through the control of cellsurface properties as shown by cell-cell sorting analyses. However, we demonstrate that only the earlier autopod cells can adopt the host proliferation rate to permit normal morphogenesis. Therefore, our findings reveal that the ability of embryonic cells to differentially reset their intrinsic behaviours confers robustness to limb morphogenesis. We speculate that this plasticity could be maintained beyond embryogenesis in limbs with regenerative capacity.

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Section: Hh20 Wings With Hh27 Grafts Have a Normal Aersupporting

confidence: 76%

Intrinsic properties of limb bud cells can be differentially reset

et al. 2017

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“…3C,D and ). This finding indicates that Shh signalling controls its own transcription in an auto-regulatory manner, possibly as part of an intrinsic timing mechanism (Chinnaiya et al, 2014). It was also evident that, by 24 h after cyclopamine treatment, wing buds were broader across the antero-posterior axis, so that by 96 h, the hand-plates of wings were increased in width by 1.2-fold (Fig.…”

Section: Resultsmentioning

confidence: 92%

“…6A). G1-phase cells have been shown to deviate by <2% in limb buds of equivalently staged embryos incubated together (Chinnaiya et al, 2014). However, there was a considerable increase in the proliferative potential of polarizing region cells after 48 h (G1 cells, 56.5% vs 72.3% in control embryos) and 72 h (68.5% vs 80.6% ; Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Shh signalling in the chick wing gives insights into digit patterning and evolution

Pickering

Towers

2016

Development

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In an influential model of pattern formation, a gradient of Sonic hedgehog (Shh) signalling in the chick wing bud specifies cells with three antero-posterior positional values, which give rise to three morphologically different digits by a self-organizing mechanism with Turing-like properties. However, as four of the five digits of the mouse limb are morphologically similar in terms of phalangeal pattern, it has been suggested that self-organization alone could be sufficient. Here, we show that inhibition of Shh signalling at a specific stage of chick wing development results in a pattern of four digits, three of which can have the same number of phalanges. These patterning changes are dependent on a posterior extension of the apical ectodermal ridge, and this also allows the additional digit to arise from the Shh-producing cells of the polarizing region – an ability lost in ancestral theropod dinosaurs. Our analyses reveal that, if the specification of antero-posterior positional values is curtailed, self-organization can then produce several digits with the same number of phalanges. We present a model that may give important insights into how the number of digits and phalanges has diverged during the evolution of avian and mammalian limbs.

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“…Initially, the involvement of Shh signaling in embryonic development of mammal species was discovered. Deprivation of certain molecules of this pathway was found to cause cerebellum atrophy and limb defects in rats (27)(28)(29)(30). Since neoplasms and embryonic development share similar molecular signaling processes, numerous studies have examined and demonstrated the core role of Shh signaling in maintaining tumor growth and cancer cell survival (12).…”

Section: Discussionmentioning

confidence: 99%

Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines

Cheng

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. The sonic hedgehog (Shh) pathway has been proven to be involved in embryonic development and cancer growth. GDC-0449, an antagonist of the hedgehog signaling receptor Smoothened (Smo), was recently approved by the US Food and Drug Administration as a prescription for skin basal cell carcinoma. However, the efficacy of GDC-0449 in the treatment of colon cancer and other malignancies, such as basal cell carcinoma and pancreatic cancer, has remained to be proven. The present study assessed the effect of GDC-0449 on the colon cancer cell lines Caco-2 and Ht-29. A Cell Counting Kit-8 assay was applied to assess the cell proliferation rate and apoptosis was tested by flow cytometry. Reverse-transcription quantitative PCR and western blot analysis were used for analyzing expression levels of target genes. Cell proliferation was inhibited, while apoptosis was increased by GDC-0449, whereas the expression of B-cell lymphoma 2 (Bcl-2), a downstream target of Shh signaling, was decreased. Consistent with the inhibition of Gli1 expression, the cancer stem cell markers CD44 and ALDH were decreased in the presence of GDC-0449. In conclusion, GDC-0449 was shown to inhibit the replication of colon cancer cells and trigger apoptosis through downregulating Bcl-2. This may also influence the stemness of cancer stem cells as indicated by the decreased stem cell surface markers.

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Sonic hedgehog-expressing cells in the developing limb measure time by an intrinsic cell cycle clock

Cited by 37 publications

References 26 publications

Intrinsic properties of limb bud cells can be differentially reset

Intrinsic properties of limb bud cells can be differentially reset

Inhibition of Shh signalling in the chick wing gives insights into digit patterning and evolution

Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines

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