Where do our limbs originate?

Christian Mosimann and other scientists are developing a new theory on limb development.

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An international team of researchers, including scientists from the University of Colorado School of Medicine, has discovered new information concerning the origin of paired appendages. This significant evolutionary transition remains unsolved and fiercely contested.

Carl Gegenbaur, a German scientist, hypothesized in 1878 that paired fins originated from the gill arch, bony loops seen in fish to support their gills. Other scientists believe that the lateral fin fold concept is correct.

Mosimann said, “It is a highly active research topic because it’s been an intellectual challenge for a long time. Many big labs have studied the various aspects of how our limbs develop and have evolved.”

Dr. Mosimann’s collaborators and co-authors include Tom Carney, Ph.D., and his team at Nanyang Technological University’s Lee Kong Chian School of Medicine.

Mosimann sees the investigation into where limbs come from as an extension of previous research undertaken by his group on the CU Anschutz Medical Campus.

In his laboratory, his team uses zebrafish as a model to study the progression of cells to organs. He and his colleagues investigate how cells pick their fate, seeking explanations for how development might go wrong, resulting in congenital malformations such as cardiovascular and connective tissue illnesses.

Mosimann and his team observed how a peculiar cell type with features of connective tissue cells, so-called fibroblasts, migrated into specific developing zebrafish fins. This suggests that these cells may support a connection between the competing theories of paired appendage evolution.

He said, “We always knew these cells were odd. There were these fibroblast-looking cells that went into the so-called ventral fin, the fin at the belly of the developing zebrafish. Similar fibroblast cells didn’t crawl into any other fin except the pectoral fin, which is the equivalent of our arms. So we kept noticing these peculiar fibroblasts, and we could never make sense of what these were for many years.”

The Mosimann lab has developed several techniques to track cell fates during development in pursuit of their main topic: a better understanding of how the embryonic cell layer, the lateral plate mesoderm, contributes to diverse organs. The lateral plate mesoderm is the developmental origin of the heart, blood vessels, kidneys, connective tissue, and major parts of the limbs.

Hannah Moran, a Ph.D. student in the Mosimann lab’s Cell Biology, Stem Cells, and Development program, altered a method for tracking lateral plate mesoderm cells that contribute to heart development so that researchers could track the unusual fibroblasts associated with limb development.

Moran said, “My primary research project focuses on the development of the heart rather than limb development, but there was a genetic technique that I had adapted to map early heart cells, and so we were able to implement that into mapping where the mysterious cells of the ventral fin came from. And it turns out they are also from the lateral plate mesoderm.”

This important discovery adds a fresh piece to how we evolved our arms and legs. Increasing evidence supports the dual origin idea, a hypothesis of paired appendage evolution.

“Our data fit nicely into this combined theory, but it can also stand on its own with the lateral fin theory.” adds postdoctoral fellow Robert Lalonde, Ph.D., of the Mosimann lab.

He said, “While paired appendages arise from the lateral plate mesoderm, that does not rule out an ancient connection to unpaired, lateral fins.”

Mosimann’s research group can build theories on how embryonic structures may have evolved or been modified over time by monitoring embryonic development mechanisms and comparing the anatomy of current species.

Mosimann said, The embryo has features that are still ancient remnants that they have not lost yet, which provides insight into how animals have evolved.”

He added, “We can use the embryo to learn more about features that persist today, allowing us to travel back in time. The body has a fundamental, inherent propensity to form bilateral, two-sided structures. Our study provides a molecular and genetic puzzle piece to resolve how we came to have limbs. It adds to this 100-plus year discussion, but now we have molecular insights.”

Mosimann’s study provides a molecular and genetic puzzle piece to resolve how we came to have limbs. International collaboration with colleagues in laboratories across the country and worldwide is also an important part of the study.

Mosimann said, “There are labs on this paper that work on musculoskeletal diseases, toxicology, fibrosis. We work on cardiovascular, congenital anomalies, cardiopulmonary anomalies, and limb development, all related to our interest in the lateral plate mesoderm.”

The researcher said, “And together, you make such fundamental discoveries. And that’s where team science enables us to do something more than just the sum of the parts.”

Collaborations with partners in laboratories around the country and around the world bring additional specialties and data from various models, such as paddlefish, African clawed frogs, and Ranchu, a split-tail goldfish variety.

The Mosimann team realizes this is an important step. However, there is more to the end of the argument about paired appendages. They have provided valuable information toward answering a crucial evolutionary conundrum.

Lalonde said, “I wouldn’t say we’ve solved the question or disproven either existing theory. Rather, we’ve contributed meaningful data towards answering a major evolutionary question.”

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