Correction: Fgf-signaling is compartmentalized within the mesenchyme and controls proliferation during salamander limb development

Purushothaman, Sruthi; Elewa, Ahmed; Seifert, Ashley W.

doi:10.7554/elife.72022

Cited by 2 publications

(7 citation statements)

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“…Fgf10 transcripts in the mesenchymal cluster (Fig. 3A, 3A’), consistent with previous reports (Christensen, Weinstein et al 2002, Nacu, Gromberg et al 2016, Purushothaman, Elewa et al 2021). Using HCR in situ hybridization we confirmed strong and broad mesenchymal expression (Fig.…”

Section: Resultssupporting

confidence: 92%

“…Along with a remarkable regenerative ability, the salamander limb presents other distinctive features in its development, both at the morphological and molecular level. The digital elements are formed in an anterior to posterior order, contrary to other species (Shubin NH 1986, Nye, Cameron et al 2003, Frobisch, Bickelmann et al 2015, Purushothaman, Elewa et al 2021. Furthermore, key molecular players of limb development, such as Fgf ligands Fgf 8, 9, and 17, exhibit divergent expression in salamander limb development and regeneration when compared to mouse and chick (Nacu, Gromberg et al 2016, Purushothaman, Elewa et al 2021) .…”

Section: Discussionmentioning

confidence: 99%

“…Little is known about the Amex.Fgf8 regulatory machinery in the axolotl limb. Amex.Fgf10 is expressed in the mesenchyme, along with Fgfs 8, 9 and 17 (Christensen, Weinstein et al 2002, Nacu, Gromberg et al 2016, Purushothaman, Elewa et al 2021. This challenges the epithelial-mesenchymal interaction model of the mammalian and avian limb where mesenchymal Fgf10 and epidermal Fgf8 reciprocally sustain each other's expression acting on different, tissue-specific, receptor isoforms.…”

Section: Introductionmentioning

confidence: 99%

“…Signaling mediated by members of the Fibroblast Growth Factor family is necessary for normal limb development and for limb regeneration in the salamander Ambystoma mexicanum (axolotl), a primary model for regeneration research (Nacu, Gromberg et al 2016, Purushothaman, Elewa et al 2021). In less-regenerative tetrapods, like mouse ( Mus musculus ), Fgf signaling is similarly required for limb development (Lewandoski, Sun et al 2000, Moon and Capecchi 2000, Sun, Mariani et al 2002, Mariani, Ahn et al 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Of the AER Fgfs, Mmu.Fgf8 is the only one that is individually required for normal limb development in mice (Mariani, Ahn et al 2008).Limb regeneration in the axolotl proceeds through the formation of the blastema, a structure that resembles the limb bud, both at the morphological and transcriptional level. In both the axolotl limb blastema and limb bud, Amex.Fgfs 8, 9 and 17 are expressed in the mesenchymal compartment, unlike in other vertebrates, while Amex.Fgf4 transcription is negligible or absent (Christensen, Weinstein et al 2002, Nacu, Gromberg et al 2016, Purushothaman, Elewa et al 2021. Restriction of Amex.Fgf8 expression to the mesenchymal compartment is to our knowledge unique to the salamander limb, where it serves a crucial role in connecting positional identity with growth and patterning during limb regeneration.…”

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confidence: 99%

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Canonical Wnt Signaling and the Regulation of Divergent Mesenchymal Fgf8 expression in Axolotl Limb Development and Regeneration

Glotzer

Tardivo

Tanaka

2022

Preprint

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The expression of Fibroblast growth factors (Fgf) ligands in a specialized epithelial compartment, the Apical Ectodermal Ridge (AER), is a conserved feature of limb development across vertebrate species. In vertebrates, Fgf 4, 8, 9, and 17 are all expressed in the AER. An exception to this paradigm is the salamander (axolotl) developing and regenerating limb, where key Fgf ligands are expressed in the mesenchyme. The mesenchymal expression of Amex.Fgf8 in axolotl has been suggested to be critical for regeneration. To date, there is little knowledge regarding what controls Amex.Fgf8 expression in the axolotl limb mesenchyme. A large body of mouse and chick studies have defined a set of transcription factors and canonical Wnt signaling as the main regulators of epidermal Fgf8 expression in these organisms. In this study, we address the hypothesis that alterations to one or more of these components during evolution has resulted in mesenchymal Amex.Fgf8 expression in the axolotl. To sensitively quantify gene expression with spatial precision, we combined optical clearing of whole-mount axolotl limb tissue with single molecule fluorescent in situ hybridization and a semi-automated quantification pipeline. Several candidate upstream components were found expressed in the axolotl ectoderm, indicating that they are not direct regulators of Amex.Fgf8 expression. We found that Amex.Wnt3a is expressed in axolotl limb epidermis, similarly to chicken and mouse. However, unlike in amniotes, Wnt target genes are activated preferentially in limb mesenchyme rather than in epidermis. Inhibition and activation of Wnt signaling results in downregulation and upregulation of mesenchymal Amex.Fgf8 expression respectively. These results implicate a shift in tissue responsiveness to canonical Wnt signaling from epidermis to mesenchyme as one step contributing to the unique mesenchymal Amex.Fgf8 expression seen in the axolotl.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Canonical Wnt Signaling and the Regulation of Divergent Mesenchymal Fgf8 expression in Axolotl Limb Development and Regeneration

Glotzer

Tardivo

Tanaka

2022

Preprint

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Variable Shh and Fgf8 positioning in regenerating axolotl limb guarantees consistent limb morphogenesis in different limb sizes

Furukawa

Yamamoto

Kashimoto

et al. 2022

Preprint

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Limb regeneration in Ambystoma mexicanum occurs in various sizes of fields and can recreate consistent limb morphology. It was not known what mechanism supports such stable limb morphogenesis regardless of size. Limb regeneration in urodele amphibians has been basically considered to recapitulate the limb developmental processes. Many molecules in the limb developmental processes are conserved with other tetrapods. SHH and FGF8 play important roles in the morphogenesis of limbs among them. Focusing on these two factors, we investigated the detailed expression pattern of Shh and Fgf8 in the various sizes of blastema in axolotl limb regeneration. Fgf8 is expressed in the anterior side of a blastema and Shh is expressed in the posterior side. These are maintained in a mutually dependent manner. We also clarified that the size of Shh and Fgf8 expression domains were scaled as the size of the blastemas increased. However, it was found that the secretion and working range of SHH were kept constant. We also found that the consistent SHH secretion range contributed to promoting cell proliferation and the first digital cartilage differentiation near the Shh expression domain. This would be a reasonable system to guarantees constant limb morphogenesis regardless of the blastema size. We also showed that the Shh-Fgf8 expression domain was shifted posteriorly as the digital differentiation progressed. Consistently, slowing the timing of blocking Shh signaling resulted in morphological defects that could be observed in only posterior digits. The revealed posteriorly shifting Shh-Fgf8 domain might explain urodele specific digit formation, in which digits are added posteriorly.

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Correction: Fgf-signaling is compartmentalized within the mesenchyme and controls proliferation during salamander limb development

Cited by 2 publications

References 0 publications

Canonical Wnt Signaling and the Regulation of Divergent Mesenchymal Fgf8 expression in Axolotl Limb Development and Regeneration

Canonical Wnt Signaling and the Regulation of Divergent Mesenchymal Fgf8 expression in Axolotl Limb Development and Regeneration

Variable Shh and Fgf8 positioning in regenerating axolotl limb guarantees consistent limb morphogenesis in different limb sizes

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