One of the primary goals in the field of comparative biology is to produce a sufficient understanding of the proficient regeneration exhibited by species such as salamanders and zebrafish to enable similar feats of complete regeneration from severe injury in mammals. Progress has been slow, as it is a challenging problem. While a number of lines of evidence suggest that mammals still possess the molecular machinery necessary to regenerate organs, such as the exceptional regenerative capacity of MRL mice, it remains unclear as to why this machinery is inactive in near all circumstances.
Tissue regeneration requires a complex cellular choreography that results in restoration of missing structures. Salamander limb regeneration is no exception, where mesenchymal cells, including dermal fibroblasts and periskeletal cells, dedifferentiate into a more embryonic-like state and migrate to the tip of the amputated limb to form a blastema. Mesenchymal cells within the blastema contain positional information which coordinates proximodistal (PD) pattern reestablishment in the regenerating limb, enabling autopod-forming blastema cells to distinguish themselves from stylopod-forming blastema cells.
It has been proposed that continuous values of positional information exist along the PD axis and that thresholds of these values specify limb segments. These segments are genetically established by combinations of homeobox genes including Hox and Meis genes, and each limb segment contains a unique epigenetic profile around these homeobox genes. However, a mechanistic explanation for how continuous values of positional information are established and differentially interpreted by limb segments during limb regeneration is lacking.
Here, we show that retinoic acid (RA) breakdown via CYP26B1 is essential for determining RA signaling levels within blastemas. CYP26B1 inhibition molecularly reprograms distal blastemas into a more proximal identity, phenocopying the effects of administering excess RA. We identify Shox as an RA-responsive gene that is differentially expressed between proximally and distally amputated limbs. Ablation of Shox results in shortened limbs with proximal skeletal elements that fail to initiate endochondral ossification. These results suggest that PD positional identity is determined by RA degradation and RA-responsive genes that regulate PD skeletal element formation during limb regeneration.
Link: https://doi.org/10.1038/s41467-025-59497-5
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