Newswise — AURORA, Colo. (May 24, 2023) –An international group involving researchers from the University of Colorado School of Medicine has revealed fresh hints regarding the source of paired appendages – a significant evolutionary advancement that remains unsettled and subject to intense discussion.
The scientists detail their investigation in a paper released today in the journal Nature.
"Although this subject has sparked some controversy, it represents an exceptionally fundamental inquiry within the field of evolutionary biology: What is the origin of our limbs?" explains Christian Mosimann, PhD, co-corresponding author, associate professor, and Johnson Chair in the Department of Pediatrics, Section of Developmental Biology at CU School of Medicine.
The inquiry – from where do our limbs originate? – has sparked discussions for over a century. In 1878, German scholar Carl Gegenbaur suggested that paired fins evolved from a structure known as the gill arch, which are skeletal rings found in fish to sustain their gills. Alternative researchers support the notion of the lateral fin fold hypothesis, positing that lateral fins situated on the upper and lower sides of the fish serve as the origin of paired fins.
"It remains a profoundly engaging subject of research due to its enduring intellectual complexity," Mosimann asserts. "Numerous prominent research facilities have dedicated their efforts to investigating the diverse facets of limb development and evolution." Among these esteemed institutions are the associates and co-writers of Dr. Mosimann, including Tom Carney, PhD, and his research group at the Lee Kong Chian School of Medicine, situated at Nanyang Technological University in Singapore.
Chasing the odd cells
For Mosimann, the investigation into the origin of limbs stems from his laboratory's broader research endeavors at the CU Anschutz Medical Campus. Within his laboratory, Mosimann's team employs zebrafish as a model organism to unravel the intricacies of cellular-to-organ development. They delve into the mechanisms behind cellular determination, seeking to elucidate the causes of developmental abnormalities, particularly those related to cardiovascular and connective tissue diseases.
During their investigations, Mosimann and his laboratory researchers made an intriguing observation. They noticed the presence of a unique cell type, resembling connective tissue cells known as fibroblasts, which shared a common developmental origin with the cardiovascular system. These fibroblasts exhibited migration into specific developing fins of the zebrafish. Remarkably, this discovery potentially establishes a link between the contrasting theories of paired appendage evolution.
"We were well aware that these cells possessed peculiar characteristics," Mosimann explains. "There were fibroblast-like cells that migrated specifically into the ventral fin, located on the belly of the developing zebrafish. Interestingly, we observed similar fibroblast cells infiltrating only one other fin—the pectoral fin, which corresponds to our arms. For years, we continued to encounter these enigmatic fibroblasts, yet we struggled to comprehend their purpose."
To delve deeper into their primary area of interest, the Mosimann laboratory has devised numerous techniques to trace the destiny of cells throughout the developmental process. Their primary objective is to enhance their comprehension of how the lateral plate mesoderm, an embryonic cell layer, contributes to the formation of various organs. It is within the lateral plate mesoderm that the heart, blood vessels, kidneys, connective tissue, and significant components of limbs originate during development. By studying this process, the lab aims to gain an improved understanding of organogenesis and its intricate cellular dynamics.
The cells originating from the lateral plate mesoderm play a crucial role in the development of the paired fins, which serve as the counterparts to our arms and legs. In contrast, other fins do not receive contributions from these cells. Unraveling the mechanisms behind the transformation of these specific fins into limb-like structures has been the focal point of a longstanding debate. Researchers have sought to gain a comprehensive understanding of the evolutionary processes and developmental factors that have shaped the limb-like characteristics of these particular fins.
Developing new theories
Hannah Moran, a PhD candidate in the Cell Biology, Stem Cells, and Development program within the Mosimann lab, has made a significant contribution to the research efforts. She ingeniously adapted a tracking method originally utilized to monitor the migration of lateral plate mesoderm cells involved in heart development. By employing this adapted technique, researchers were able to track the peculiar fibroblasts specifically associated with limb development. This innovative approach has provided valuable insights into the behavior and fate of these unique cells during the intricate process of limb formation.
"While my primary research project primarily revolves around studying heart development," Moran explains, "I had previously adapted a genetic technique to map early heart cells. We saw an opportunity to apply this technique to trace the origin of the enigmatic cells in the ventral fin. Surprisingly, our findings revealed that these cells also originate from the lateral plate mesoderm, similar to the cells involved in heart development." Moran's expertise in mapping early heart cells proved invaluable in shedding light on the origins of the mysterious cells present in the ventral fin, further connecting them to the lateral plate mesoderm.
This significant discovery serves as a valuable addition to the larger puzzle of limb evolution, offering a new piece of the picture. The mounting evidence provides support for a hypothesis known as the dual origin theory, which posits that paired appendages, such as our arms and legs, have evolved from multiple origins. The newfound understanding of the origin of the peculiar cells related to limb development further strengthens the case for this hypothesis, bringing us closer to unraveling the complex mechanisms underlying the evolution of our limbs.
"Our data align well with the combined theory of limb evolution, but it can also independently support the lateral fin theory," explains Robert Lalonde, a postdoctoral fellow in the Mosimann lab. "While it is evident that paired appendages originate from the lateral plate mesoderm, this does not necessarily negate the possibility of an ancient connection to unpaired lateral fins. Our findings provide compelling evidence for the involvement of lateral plate mesoderm cells in limb development, while still leaving room for an intriguing connection between paired and unpaired fins in the evolutionary history of appendages."
Through meticulous examination of embryonic development mechanisms and comparative analysis of anatomical features across various species, research groups like Mosimann's are able to formulate theories regarding the evolution and modification of embryonic structures over time. By studying the intricate processes of development and analyzing the similarities and differences in anatomy among different organisms, researchers can gain insights into the evolutionary history of these structures. This approach allows them to develop theories and hypotheses that shed light on the evolutionary transformations that have shaped the development of organisms throughout history.
"The embryo retains certain features that serve as ancient remnants, reflecting the evolutionary history of animals," explains Mosimann. "By studying the embryo, we can gain valuable insights into the persistence of certain characteristics that have endured over time. It allows us to essentially travel back in time and understand more about the evolutionary processes that have shaped organisms. One intriguing observation is that the body has an inherent inclination to develop bilateral, two-sided structures. Our study offers a molecular and genetic puzzle piece that contributes to resolving the mystery of how limbs evolved. It adds a new dimension to the ongoing discussion that has spanned over a century, providing us with valuable molecular insights into this complex process."
International collaboration
Collaborations with colleagues in laboratories spanning across the country and around the globe play a crucial role in advancing this field of study. These collaborations allow researchers to tap into additional specializations and gather data from various model organisms. In the study of embryonic development, scientists often work with a range of species, including paddlefish, African clawed frogs, and a variant of split-tail goldfish known as Ranchu. Each of these organisms provides unique insights and contributes valuable information to our understanding of embryonic development. By pooling together their expertise and data from diverse models, researchers can gain a more comprehensive and holistic understanding of the intricate processes underlying embryogenesis.
The collaborative efforts showcased in this paper involve a range of laboratories with diverse focuses such as musculoskeletal diseases, toxicology, and fibrosis. Mosimann's lab, specifically, concentrates on cardiovascular studies, congenital anomalies, cardiopulmonary anomalies, and limb development, all interconnected through their shared interest in the lateral plate mesoderm. By combining the expertise and research interests of these multidisciplinary teams, significant and fundamental discoveries become possible. The power of team science lies in its ability to create a synergy that surpasses the individual contributions, enabling researchers to achieve more comprehensive and impactful outcomes than what could be accomplished by individual efforts alone.
Despite the substantial effort and importance of the study, the Mosimann team acknowledges that it represents a pivotal stage, but not the conclusive culmination, in the ongoing debate regarding paired appendages.
"I wouldn't claim that we have definitively solved the question or disproven either of the existing theories," Lalonde explains. "Instead, we have provided significant data that contributes to addressing a major evolutionary inquiry."
About the University of Colorado School of Medicine
Faculty at the University of Colorado School of Medicine work to advance science and improve care. These faculty members include physicians, educators and scientists at UCHealth University of Colorado Hospital, Children’s Hospital Colorado, Denver Health, National Jewish Health, and the Veterans Affairs Eastern Colorado Health Care System. The school is located on the Anschutz Medical Campus, one of four campuses in the University of Colorado system.
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