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    Where do our limbs come from?    
      
     Date:   
         May 24, 2023   
     Source:   
         University of Colorado Anschutz Medical Campus   
     Summary:   
         Scientists have uncovered new clues about the origin of paired   
         appendages -- a major evolutionary step that remains unresolved   
         and highly debated.   
      
      
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   FULL STORY   
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   An international collaboration that includes scientists from the   
   University of Colorado School of Medicine has uncovered new clues about   
   the origin of paired appendages -- a major evolutionary step that remains   
   unresolved and highly debated.   
      
   The researchers describe their study in an article published today in   
   the journal Nature.   
      
   "This has become a topic that comes with bit of controversy, but it's   
   really 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 CU School of Medicine.   
      
   That question -- where do our limbs come from? -- has been subject of   
   debate for more than 100 years. In 1878, German scientist Carl Gegenbaur   
   proposed that 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, concluding that lateral   
   fins on the top and bottom of the fish are the source of paired fins.   
      
   "It is a highly active research topic because it's been an intellectual   
   challenge for such a long time," Mosimann says. "Many big labs   
   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 at the Lee Kong Chian School of Medicine   
   at Nanyang Technological University in Singapore.   
      
   Chasing the odd cells For Mosimann, the inquiry into where limbs come   
   from is an offshoot of other research conducted by his laboratory on the   
   CU Anschutz Medical Campus. In his laboratory, his team uses zebrafish   
   as a model to understand the development from cells to organs. He and   
   his team study how cells decide their fate, looking for explanations   
   for how development can go awry leading to congenital anomalies, in   
   particular cardiovascular and connective tissue diseases.   
      
   Along the way, Mosimann and his lab team observed how a peculiar cell   
   type with features of connective tissue cells, so-called fibroblasts that   
   share a developmental origin with the cardiovascular system, migrated   
   into specific developing fins of the zebrafish. It turns out that these   
   cells may support a connection between the competing theories of paired   
   appendage evolution.   
      
   "We always knew these cells were odd," he says. "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 are 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, which is an improved   
   understanding of how the embryonic cell layer, called the lateral plate   
   mesoderm, contributes to diverse organs. The lateral plate mesoderm is   
   the developmental origin of the heart, blood vessels, kidneys, connective   
   tissue, as well as major parts of limbs.   
      
   The paired fins that form the equivalent of our arms and legs are   
   seeded by cells from the lateral plate mesoderm, while other fins are   
   not. Understanding how these particular fins became more limb-like has   
   been at the core of a long- standing debate.   
      
   Developing new theories Hannah Moran, who is pursuing her PhD in the Cell   
   Biology, Stem Cells and Development program in the Mosimann lab, adapted a   
   method of tracking lateral plate mesoderm cells that contribute to heart   
   development so that researchers could track the peculiar fibroblasts   
   related to limb development.   
      
   "My primary research project focuses on the development of the heart   
   rather than limb development," Moran says, "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 turns out, they are also from the lateral plate   
   mesoderm."  This crucial discovery provides a new puzzle piece to the big   
   picture of how we evolved our arms and legs. Increasing evidence supports   
   a hypothesis of paired appendage evolution called the dual origin theory.   
      
   "Our data fit nicely into this combined theory, but it can also stand   
   on its own with the lateral fin theory," says Robert Lalonde, PhD,   
   postdoctoral fellow in the Mosimann lab. "While paired appendages arise   
   from the lateral plate mesoderm, that does not rule out an ancient   
   connection to unpaired, lateral fins."  By observing the mechanisms of   
   embryonic development and comparing the anatomy of existing species,   
   research groups like Mosimann's can develop theories on how embryonic   
   structures may have evolved or have been modified over time.   
      
   "The embryo has features that are still ancient remnants that they have   
   not lost yet, which provides insight into how animals have evolved,"   
   Mosimann says.   
      
   "We can use the embryo to learn more about features that just persist   
   today, allowing us to kind of travel back in time," Mosimann says. "We see   
   that 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."  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 specializations and contribute   
   data from other models, including paddlefish, African clawed frogs,   
   and a variant of split-tail goldfish called Ranchu, to study embryonic   
   development.   
      
   "There are labs on this on this paper that work on musculoskeletal   
   diseases, toxicology, fibrosis. We work on cardiovascular, congenital   
   anomalies, cardiopulmonary anomalies, limb development, all related to   
   our interest on the lateral plate mesoderm," says Mosimann. "And then   
   together, you get to make such fundamental discoveries. And that's where   
   team science enables us to do something that is more than just the sum   
   of the parts."  For all the considerable work and significance of the   
   study, the Mosimann team recognizes that it is a key step, but not the   
   end of the journey in the debate about paired appendages.   
      
   "I wouldn't say we've solved the question, or even disproven either   
   existing theory," says Lalonde. "Rather, we've contributed meaningful   
   data towards answering a major evolutionary question."   
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Stem_Cells # Immune_System # Pregnancy_and_Childbirth   
             o Plants_&_Animals   
                   # Developmental_Biology # Biology # Biotechnology   
             o Fossils_&_Ruins   
                   # Charles_Darwin # Evolution # Origin_of_Life   
       * RELATED_TERMS   
             o Recent_single-origin_hypothesis o Natural_selection o   
             Smallpox o Convergent_evolution o Evolutionary_psychology   
             o The_evolution_of_human_intelligence o Tooth_enamel o   
             Timeline_of_human_evolution   
      
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   Story Source: Materials provided by   
   University_of_Colorado_Anschutz_Medical_Campus. Original written by Mark   
   Couch. Note: Content may be edited for style and length.   
      
      
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   Journal Reference:   
      1. Keh-Weei Tzung, Robert L. Lalonde, Karin D. Prummel, Harsha   
         Mahabaleshwar, Hannah R. Moran, Jan Stundl, Amanda N. Cass, Yao   
         Le, Robert Lea, Karel Dorey, Monika J. Tomecka, Changqing Zhang,   
         Eline C.   
      
         Brombacher, William T. White, Henry H. Roehl, Frank J. Tulenko,   
         Christoph Winkler, Peter D. Currie, Enrique Amaya, Marcus C. Davis,   
         Marianne E.   
      
         Bronner, Christian Mosimann, Tom J. Carney. A median fin   
         derived from the lateral plate mesoderm and the origin of paired   
         fins. Nature, 2023; DOI: 10.1038/s41586-023-06100-w   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/05/230524181858.htm   
      
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