2025/06/01 by M. Bakker, Luthfi Nurhidayat, Alisha Kiran Dijkerman +5 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Cleft Lip and Palate Research #Hedgehog Signaling Pathway Studies #Prenatal Screening and Diagnostics
paper · pdf · doi:10.1093/molbev/msaf113
openalex publication_date 2025/06/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/29
Amniotes show a great diversity of limb phenotypes, including limbs specialized for running, flying, swimming, and digging. Here, we have examined how this diversity is generated during limb development in 13 species using transcriptomics and in situ hybridization. The selected species show evolutionary changes in the number of phalanges and/or loss of claws. We first looked at genes that show cyclical expression during digit development. Significantly, we find that Gdf5 cycles more rapidly in digits developing more phalanges. We identified two novel cyclically expressed genes: Ackr3 and Wnt9a. We also identified a transition point at which phalanx formation stops and claw development begins. We found that this transition point is marked by the downregulation of multiple developmental genes in the phalanx-forming region, and upregulation of claw-related genes. The timing of this transition is conserved, taking place at the same developmental stage in all digits of all species examined-except in the clawless digits of the Chinese soft-shelled turtle, the crocodilians, and birds. We suggest a model based on transcriptional heterochrony, in which the frequency of phalanx formation and the timing of the phalanx-claw transition are evolutionary control points open to natural selection on the phenotype. Furthermore, our model suggests that relaxation of developmental constraints on the timing of the phalanx-claw transition allows the digits to develop more phalanges (hyperphalangy). This is seen in some turtles, crocodilians, and dolphins. More broadly, our findings are consistent with the hypothesis that "hotspots" in otherwise conserved developmental pathways may be targets for evolutionary tinkering.