Where do our limbs come from? — Daily Science

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The researchers describe their study in an article published today in the journal Nature.

“This has become a bit of a controversial topic, but it’s actually a very fundamental question in evolutionary biology: Where do our limbs come from?” says co-corresponding author Christian Mosimann, PhD, associate professor and Johnson Chair in the Department of Pediatrics, Section of Developmental Biology at the CU School of Medicine.

That question: where do our limbs come from? — has been the subject of debate for more than 100 years. In 1878, the German scientist Carl Gegenbaur proposed that the paired fins derived from a source called the gill arch, which are bony loops present in fish to support their gills. Other scientists favor the lateral fin fold hypothesis and conclude that the lateral fins on the top and bottom of the fish are the source of the paired fins.

“It’s a very active research topic because it’s been an intellectual challenge for a long time,” says Mosimann. “Many large laboratories have studied the various aspects of how our limbs develop and have evolved.” Among those labs are Dr. Mosimann’s colleagues and co-authors Tom Carney, PhD, and his team from the Lee Kong Chian School of Medicine at Nanyang Technological University in Singapore.

Chasing the odd cells

For Mosimann, the research on the origin of limbs is an offshoot of other research conducted by his lab on the CU Anschutz medical campus. In her lab, her team uses zebrafish as a model to understand the development from cells to organs. He and his team study how cells decide their fate, seeking explanations for how development can go awry and lead to birth defects, particularly cardiovascular and connective tissue diseases.

Along the way, Mosimann and his lab team observed how a peculiar cell type with characteristics of connective tissue cells, so-called fibroblasts that share a developmental origin with the cardiovascular system, migrated into the developing fins specific to zebrafish. . It turns out that these cells may support a connection between competing theories of the evolution of paired appendages.

“We always knew these cells were weird,” he says. “There were these cells that looked like fibroblasts that went into the so-called ventral fin, the fin on the belly of the developing zebrafish. Similar fibroblast cells didn’t crawl into any other fins except the pectoral fin, which are the equivalent of our arms. So we kept noticing these peculiar fibroblasts, and we were never able to understand what they were for many years.”

Mosimann’s lab has developed several techniques to trace the fate of cells during development in search of their main theme, which is a better understanding of how the embryonic cell layer, called the lateral plate mesoderm, contributes to various organs. The lateral plate mesoderm is the origin of the development of the heart, blood vessels, kidneys, connective tissue, as well as most of the extremities.

The paired fins that form the equivalent of our arms and legs are seeded by cells of the lateral plate mesoderm, while other fins are not. Understanding how these particular fins became more limb-like has been at the center of a long-standing debate.

Development of new theories

Hannah Moran, who is doing her PhD in the Cell Biology, Stem Cells and Development program in Mosimann’s lab, adapted a method to track the lateral plate mesoderm cells that contribute to heart development so that researchers could track the peculiar fibroblasts related to limb development.

“My main research project is focused on heart development rather than limb development,” says Moran, “but there was a genetic technique that I had adapted to map early heart cells, and we were able to implement that into mapping where the cells came from.” mystery cells from the ventral fin. And it turns out they’re also from the side plate mesoderm.”

This crucial discovery provides a new puzzle piece to the big picture of how our arms and legs evolved. Mounting evidence supports a hypothesis of paired appendage evolution called the dual origin theory.

“Our data fit this combined theory very well, but they can also stand on their own with the lateral fin theory,” says Robert Lalonde, PhD, a postdoctoral fellow in Mosimann’s lab. “While the paired appendages arise from the lateral plate mesoderm, that does not rule out an ancient connection to the unpaired lateral fins.”

By looking at the mechanisms of embryonic development and comparing the anatomy of extant species, research groups like Mosimann’s can develop theories about how embryonic structures may have evolved or changed over time.

“The embryo has features that are still ancient remnants that have not yet been lost, which provides insight into how animals have evolved,” Mosimann says. “We can use the embryo to learn more about features that still persist today, allowing us to travel back in time,” Mosimann says. “We see that the body has a fundamental and inherent propensity to form bilateral, two-sided structures. Our study provides a piece of the molecular and genetic puzzle for how we came to have limbs. It adds to this discussion of more than 100 years, but now we have molecular knowledge.”

international collaboration

Collaborations with colleagues in laboratories across the country and around the world are another important part of the study. Those scientists bring additional expertise and contribute data from other models, including paddlefish, African clawed frogs, and a split-tailed goldfish variant called Ranchu, to study embryonic development.

“There are laboratories in this article that work on musculoskeletal diseases, toxicology, fibrosis. We work on cardiovascular abnormalities, congenital abnormalities, cardiopulmonary abnormalities, limb development, all related to our interest in lateral plate mesoderm,” says Mosimann. “And then, together, they can make such fundamental discoveries. And that’s where team science allows us to make something that’s more than the sum of its parts.”

Despite the considerable work and importance of the study, Mosimann’s team acknowledges that it is a key step, but not the end of the journey, in the debate over paired appendages.

“I wouldn’t say that we have solved the question, or even disproved any of the existing theories,” says Lalonde. “Rather, we have contributed meaningful data to answer an important evolutionary question.”