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

Abstract

Although decades of studies have produced a generalized model for tetrapod limb development, urodeles deviate from anurans and amniotes in at least two key respects: their limbs exhibit preaxial skeletal differentiation and do not develop an apical ectodermal ridge (AER). Here, we investigated how Sonic hedgehog (Shh) and Fibroblast growth factor (Fgf) signaling regulate limb development in the axolotl. We found that Shh-expressing cells contributed to the most posterior digit, and that inhibiting Shh-signaling inhibited Fgf8 expression, anteroposterior patterning, and distal cell proliferation. In addition to lack of a morphological AER, we found that salamander limbs also lack a molecular AER. We found that amniote and anuran AER-specific Fgfs and their cognate receptors were expressed entirely in the mesenchyme. Broad inhibition of Fgf-signaling demonstrated that this pathway regulates cell proliferation across all three limb axes, in contrast to anurans and amniotes where Fgf-signaling regulates cell survival and proximodistal patterning.

The genome of the bowfin (Amia calva) illuminates the developmental evolution of ray-finned fishes

“…[92][93][94][95][96] ) and is critical for the outgrowth and patterning of these appendages. Even in species that lack a morphological AER, fgf8 is still expressed [97][98][99] . Thus, the lack of fgf8 from the holostean n bud is entirely unexpected.…”

Parallels between wound healing, epimorphic regeneration and solid tumors

“…The accumulated cells within the blastema undergo sustained proliferation to produce all the cells contained within the regenerated limb (Whited and Tabin, 2009). Blastema formation is then followed by patterning, during which cells within the blastema differentiate, establish a positional identity and organize into functional structures (McCusker et al, 2014;Purushothaman et al, 2019). Overall, epimorphic regeneration is distinct from typical wound healing because it relies on the formation and outgrowth of the blastema.…”

The giant axolotl genome uncovers the evolution, scaling, and transcriptional control of complex gene loci

“…It is currently unknown whether and how such long-distance regulation and TAD organization may occur in the axolotl in the face of a roughly 13-fold larger genome. It is also an open question whether adaptations related to these large genomic distances could contribute to characteristic aspects of their limb development ( 13 – 15 ). For example, the conserved, long-range regulatory elements controlling Fgf8 gene expression in the apical ectodermal ridge of the mouse limb bud have been extensively characterized and act over 200 Kb ranges ( 8 ).…”