Introduction: The Mystery Behind a Flying Mammal
Bats are the only mammals capable of true powered flight. Their wings differ dramatically from the typical mammalian limb, yet they sprouted from the same five-digit limb pattern found in mice, humans, and dolphins. How did evolution turn a familiar blueprint into a remarkable flying apparatus?
Early expectations held that major biological leaps required big genetic differences. But as genome sequencing advanced, researchers found that most mammals share the same toolkit of genes. The question then became: how do identical genes, used in similar embryonic stages, produce such diverse limbs?
Regulatory Evolution, Not New Genes
The answer lies in regulatory evolution — changes in when, where, and how genes are switched on during development. A team led by Christian Feregrino and Magdalena Schindler investigated how regulatory shifts contribute to the bat wing known as the chiropatagium, a thin skin sheet spanning between bat digits that forms the wing’s surface.
Using an unprecedented “interspecies limb atlas,” they analyzed over 180,000 embryonic limb cells from bats (Carollia perspicillata) and mice at key developmental stages. This fusion of single-cell RNA sequencing with genomics allowed them to trace cell populations responsible for bone, muscle, connective tissue, and skin, and compare their trajectories across species.
The Surprising Cellular Reality
Contrary to expectations, bat and mouse limbs were strikingly similar at the cellular level. The same cell types appear across development, whether the limb becomes a paw or a wing. In both species, genes associated with programmed cell death, such as Aldh1a2 and Bmp2, remained active in the tissue between the digits. This held true even in bats, where the chiropatagium persists, suggesting that interdigital cell death continues to sculpt the digits even as wing skin forms.
Delving deeper, researchers dissected the chiropatagium region and performed targeted single-cell analyses. They uncovered a specialized population of fibroblasts — connective tissue cells — present only in bat forelimbs, specifically between the digits. Rather than inventing an entirely new cell type, evolution repurposed an existing fibroblast population, typically located nearer the shoulder in mice, for deployment between the digits in bats.
These bat fibroblasts showed high activity of two transcription factors, MEIS2 and TBX3. In most mammals, these genes are silenced before finger formation; in bats, they are reactivated near the developing digits, contributing to the distinctive wing tissue. This is a striking example of evolutionary co-option: repurposing existing genetic programs to build novel structures without inventing new cell types.
Testing the Idea in Mice
To test whether these genes could drive wing-like features, the team engineered transgenic mice to express bat versions of MEIS2 and TBX3 in the distal limb and interdigital tissues. They used a DNA enhancer to activate these genes in the fingers and the webbing between them. The results were compelling: mouse embryos developed webbed digits, thicker interdigital tissue, and even expression of other genes characteristic of bat wing fibroblasts. Three-dimensional limb imaging revealed fused digits and expanded hand connective tissue — key hallmarks of a developing bat wing.
“With just these two transcription factors, we could partly recapitulate the bat’s wing-building program,” said Dr. Feregrino. While this does not turn a mouse into a bat—flight requires coordinated changes across bones, muscles, tendons, and skin—it demonstrates how regulatory shifts can power major morphological innovations.
Broader Implications: From Bats to Other Wings
The study illuminates a broader evolutionary principle: many complex structures arise not from new genes but from reusing and re-tuning existing gene networks. This mechanism could underpin how birds perfected wings, fishes refined fins, and whales sculpted flippers, all by tweaking regulatory switches within a shared developmental playbook.
Beyond evolution, the findings may inform medical research into developmental disorders. Conditions like syndactyly, where fingers fail to separate, could share regulatory pathways with wing formation, guiding future diagnoses or therapies as scientists map how gene activity shapes digit separation.
As single-cell technologies advance, researchers anticipate uncovering more cases where evolution creatively repurposes old genes, revealing the flexible nature of development and the ingenuity of natural selection.
