Bats are the only mammals capable of true powered flight, yet their wings have evolved from the same basic five-digit limb structure found in all mammals. How, then, can they alone fly?
“At first, when scientists started comparing animals, we thought big anatomical differences must come from big differences in DNA,” Christian Feregrino, a lead co-author of a new study published in Nature Ecology & Evolution that has found how.
“But as more genomes were sequenced, we realised mammals share most of the same genes. Embryos, too, look very, very similar in early stages — you can’t tell a bat from a mouse or even a dolphin. So the question became: how do the same genes, starting from the same blueprint, produce such different limbs?”
“The answer lay in what scientists call regulatory evolution: changing when, where, and how genes are switched on.”
The chiropatagium mystery
Mammals usually have forelimbs that form arms or legs with five fingers or toes. In bats, these limbs have changed a lot over time. Digits (fingers) two through five are stretched out and connected by a thin sheet of skin called the chiropatagium, which makes up most of the wing’s surface for flying.
Scientists have long wondered how bats keep this skin between their fingers. In other mammals, like humans or mice, the skin between the fingers disappears before birth in a process where the cells die on purpose, called apoptosis. One leading hypothesis is that bats evolved flight by suppressing this interdigital cell death, which allowed the skin to stay and form the wing’s surface.
The new study painted a more nuanced picture, however.
To test whether bats really did suppress apoptosis in the developing wing, the researchers built an “interspecies limb atlas” using single-cell RNA sequencing, plus other genomic tools, on more than 180,000 cells from embryonic limb tissue from bats (Carollia perspicillata) and mice at various stages of development.
This allowed them to map every major cell population in the limb across key developmental stages, including those responsible for bone, muscle, connective tissue, and skin, and compare the results using computational models and statistical analyses.
“We expected to find special, unique cells in bats that form the chiropatagium,” Magdalena Schindler, a co-lead author of the paper, said. “But our first big surprise was that, at the cellular level, bat and mouse limbs are almost identical. The same cell types appear throughout development, whether the limb becomes a paw or a wing.”
In both species, genes linked to cell death, such as Aldh1a2 and Bmp2, were active in the tissue between the fingers, even in bats where the chiropatagium persisted. This meant cell death still happened, challenging the hypothesis that wing tissue is retained because cell death is inhibited.
Digging deeper, the team performed targeted single-cell analysis of the chiropatagium itself by dissecting and sequencing the genetic material in cells from that region in bat embryos. They found a specialised population of fibroblasts — connective tissue cells — present only in bat forelimbs and between the fingers.
That is, instead of inventing a new cell type, evolution had repurposed an existing one normally found closer to the shoulder in mice. In bats, these cells are deployed between the digits while the surrounding cells still undergo apoptosis that sculpts separate fingers.
These fibroblasts showed high activity of two transcription factors, MEIS2 and TBX3. In other mammals, these genes are switched off before fingers form. In bats, they are switched back on in the distal limb near the developing digits.
“They’d been spotted before in developing bat wings, but no one knew their role,” Dr. Schindler said. “Our analysis now connects them to the identity of this specific fibroblast population, showing that they are central components of the genetic program that gives these cells their identity and may influence how apoptosis is regulated.”
This kind of genetic redeployment, known as evolutionary co-option, allows organisms to build new structures by using existing gene programmes rather than inventing new ones.
Testing in mice
But could these genes really drive wing formation on their own?
To test this, the researchers engineered transgenic mice to express bat versions of the genes MEIS2 and TBX3 in the distal limb and interdigital tissues, where they’re usually silent. They used a special DNA enhancer that activated these genes in the developing fingers and the webbing between them.
The result: mouse embryos began to grow webbed digits and the tissue between their fingers became thicker and more structured, much like an early bat wing. Cells in the webbing also began expressing other genes found in bat wing fibroblasts.
These changes weren’t just molecular. When researchers imaged the limbs in 3D, they saw clear physical differences. The modified mice had fused digits and expanded connective tissue in the hand area, both hallmarks of the bat chiropatagium.
“With just these two transcription factors, we could partially recapitulate the bat’s wing-building program,” Dr. Feregrino said. “It’s a long way from turning a mouse into a bat, as flight requires coordinated changes in bones, muscles, skin, and more. But the findings show how powerful these regulatory shifts can be.”
Beyond bats
While the researchers weren’t aiming for medical applications, the findings could help understand human developmental disorders. Syndactyly, a congenital condition where fingers remain fused, may share mechanisms with bat wing formation. Knowing which genes influence digit separation could help better diagnose or even treat such conditions.
“The study also offers clues to other evolutionary puzzles,” Dr. Feregrino said. “Bird wings, fish fins, and whale flippers may all follow a similar strategy: start with a universal developmental plan, then tweak specific genetic ‘dials’ to create new forms.”
“With single-cell tools, we expect to uncover many more ways evolution repurposes old genes creatively,” Dr. Schindler added.
Manjeera Gowravaram has a PhD in RNA biochemistry and works as a freelance science writer.
