To distinguish between the top and the bottom side of our limbs, nature “redeployed” ancient genes from the midline fins of fish. This is the conclusion of an international research team led by Konstanz-based biologist Joost Woltering.

How did the complexity of many organisms living today evolve from the simpler body plans of their ancestors? This is a central question in biology. Take our hands, for example: Every time we type a message on our mobile phone, we are using an evolutionary “masterpiece” that evolved over millions of years. Notably, we typically grasp and manipulate objects with the palm of our hand – its ventral side. The back of our hand, or dorsal side, plays almost no role. This differentiation of our limbs, with a ventral side adapted for contact and a dorsal side protected by fingernails or toenails, is essential for life on land.

But how does nature distinguish between the top and the bottom sides of a limb, and which adjustments to the genetic machinery were necessary during evolution to make this possible? An international research team led by Konstanz-based biologist Joost Woltering has the answers. In their recent article in Molecular Biology and Evolution, they describe how ancient genes from the midline fin of fish had to be “redeployed” to establish the dorsal-ventral axis in our limbs.

An anatomical puzzle
The evolutionary journey from ancient fins to the human hand began roughly 500 million years ago. Around that time, the genetic programme for fins typically found on a fish’s back – the midline fins – was copied and activated on the flank of one of our aquatic ancestors. This gave rise to the first fish with paired fins. About 350 million years ago, these paired fins evolved into the paired limbs of vertebrates, including our arms and legs.

Accordingly, there are many genetic similarities between the midline fins of fish and our limbs. “For instance, in the midline fins of fish we can detect the same genetic signals that, in our own hand, specify the thumb and the pinky finger”, explains Joost Woltering. However, when it comes to distinguishing the top and bottom sides of our limbs, a puzzle emerges: Ancient midline fins, such as the iconic fins of sharks, have an identical left and right side. An equivalent to our palm and the back of our hand does not exist in these fins.

A gene acquires a new function
It was already known that during embryonic development, a gene called Lmx1b plays a crucial role in shaping our hands: Cells in which the gene is active become the back of the hand, whereas cells in which it is inactive develop into the palm. To find out what role this gene played in ancient midline fins, the research team investigated Lmx1b activation in various fish species – from cichlids to sharks.

Their results revealed a striking difference in Lmx1b activation between fin types: In paired fins – the more direct precursor of our limbs – the gene is active on the dorsal surface, just as it is in our hands. In midline fins, however, it is activated toward the rear of the fin – the end facing away from the head. “This activation pattern in midline fins was completely unexpected. It suggests that while the gene was present in ancient fins, its original function was unrelated to distinguishing between top and bottom”, says Woltering.

Guiding neurons as the ancient function
To understand how this functional shift occurred, the researchers also investigated what triggers Lmx1b activity in different fin types – and again discovered clear differences. In paired fins, Lmx1b activity is triggered by what is known as Wnt signaling, whereas in ancient midline fins it is triggered by so-called Hedgehog signalling. When Wnt signalling was experimentally switched off in fish embryos, Lmx1b activity disappeared in the paired lateral fins, but not in the midline fins. “This means that nature not only had to copy and redeploy the Lmx1b gene to create the dorsal side of our hands, but also had to evolve entirely new regulatory switches”, Woltering explains.

This leaves one final question: What was the original function of Lmx1b in midline fins? The researchers found an answer to this as well. In addition to defining the dorsal-ventral axis in our limbs, Lmx1b activates receptor molecules that guide motor neurons to the correct muscles during embryonic development. This precise wiring allows us, for example, to extend and flex our limbs through separate nerve pathways. “Our results suggest that the ancestral function of the Lmx1b signal in midline fins was to ensure the proper neuronal wiring of the posterior fin musculature”, says Woltering.

Key facts:

• Original publication: S. Zdral, S.G. Bordignon, A. Meyer, M.A. Ros, J.M. Woltering (2026) Dorsoventral limb patterning in paired appendages emerged via regulatory repurposing of an ancestral posterior fin module. Molecular Biology and Evolution; doi: 10.1093/molbev/msaf331
• An international research team led by Joost Woltering describes the genetic basis of a key innovation in the evolution of our limbs from the ancient midline fins of fish.
• Researchers and institutions involved:
  • Joost Woltering, Axel Meyer, and Simone Giulio Bordignon (University of Konstanz, Germany)
  • Sofía Zdral and Marian A. Ros (University of Cantabria, Santander, Spain)
• Press contact: Joost Woltering, Department of Biology, University of Konstanz, phone +(49) 7531 88 2763, email: joost.woltering@uni-konstanz.de
• Funding: German Research Foundation (DFG), Spanish Ministry of Science and Innovation (MICIU), European Molecular Biology Organization (EMBO) and University of Konstanz