The evolutionary origin of the vertebrate kidney may differ from what scientists have long believed. A study published in the journal Science Advances presents new evidence supporting a scientific hypothesis first proposed in 1888 but never widely accepted. According to the researchers, the first cells that form the embryonic kidney do not arise solely from the embryonic tissue traditionally regarded as their source. Instead, they originate from a region of the embryo that also gives rise to the body's muscles, tendons, vertebral column, and other parts of the axial skeleton.
"This finding is more than a minor revision to the evolutionary model of kidney development," said Dr. Ram Reshef of the University of Haifa. "It changes the way we examine relationships between different body systems at the earliest stages of embryonic development, showing that processes once thought to be separate may be far more deeply connected from an evolutionary perspective."
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The first cells that form the embryonic kidney do not arise solely from the embryonic tissue traditionally regarded as their source
(Photo: Dr. Ram Reshef)
To understand the significance of the discovery, it is necessary to look at a very early stage of embryonic development, long before the kidney assumes its familiar form. In vertebrates, the kidney develops in stages. The first to appear is the embryonic kidney, which forms near the front of the embryo at the boundary between the head and the neck. Additional stages of kidney development follow, eventually leading to the mature kidney found in mammals, birds, and reptiles.
For decades, the prevailing view has been that this process begins in a narrow strip of embryonic tissue known as the intermediate mesoderm, which also gives rise to the reproductive organs. In the new study, Dr. Reshef, doctoral student Pascal Schmidt, members of Dr. Reshef's laboratory in the Department of Evolutionary and Environmental Biology at the University of Haifa, and collaborators from the Technion, Sorbonne University in France, and the University of Genoa in Italy set out to determine the embryonic and evolutionary origin of the earliest kidney, identify the molecular mechanisms regulating its development, and test whether the conventional model accurately describes the beginning of the process.
Embryo of the lancelet (Branchiostoma lanceolatum), a small marine animal closely related to vertebrates but not itself a vertebrate
(Photo: Dr. Ram Reshef)
The researchers adopted a comparative approach, studying embryos from three species representing key stages in vertebrate evolution. The first was the lancelet (Branchiostoma lanceolatum), a small marine animal closely related to vertebrates but not itself a vertebrate, offering a glimpse into an early stage of vertebrate body evolution. The second was the European river lamprey (Lampetra fluviatilis), a jawless fish representing one of the earliest vertebrate lineages. The third was the small-spotted catshark (Scyliorhinus canicula), a cartilaginous fish with jaws that represents another early branch in vertebrate evolution.
The team tracked the expression of early molecular markers of kidney development, including the genes Pax2 and Lim1, to determine precisely where they appeared in the embryos of each species. They also carried out functional experiments by blocking the Sonic hedgehog signaling pathway—one of the key regulatory mechanisms in embryonic development—to test whether the same pathway that controls development of the vertebral column and axial skeleton also influences the earliest stages of kidney formation. By combining evolutionary comparisons across multiple early-diverging species with molecular labeling and advanced imaging, the researchers were able to trace the process not only by tissue morphology but also by the molecular identity of individual cells.
Embryo of the lancelet (Branchiostoma lanceolatum), a small marine animal closely related to vertebrates but not itself a vertebrate
(Photo: Dr. Ram Reshef)
The findings showed that in both shark embryos and lamprey embryos, the first cells that give rise to the embryonic kidney are located within the somite, a repeating embryonic structure that serves as the source of several major tissues, including muscles, the skin of the back, tendons, and parts of the skeleton. The researchers identified this region as the nephrotome—the embryonic domain from which the kidney develops.
The authors conclude that the somite is not solely involved in the development of the musculoskeletal system but also contains the region from which the earliest kidney cells emerge. They further found that blocking Sonic hedgehog signaling—already known to regulate development of the vertebral column—also disrupted formation of the embryonic kidney in sharks and lampreys, but not in the lancelet, which lacks vertebrae. This suggests a developmental link between the vertebral column and the earliest kidney.
Embryo of European river lamprey (Lampetra fluviatilis), a jawless fish representing one of the earliest vertebrate lineages
(Photo: Dr. Ram Reshef)
The findings indicate that, during evolution, not only did the cellular origin of the kidney change, but so did the regulatory mechanisms controlling its development.
"The importance of this discovery lies in the new questions it allows us to ask about how the body is built," Dr. Reshef said. "If the earliest stages of kidney development are linked to the same embryonic region that also forms components of the skeleton, this may eventually help us better understand conditions in which kidney and skeletal defects occur together. This is not a promise of a medical treatment, but rather a deeper understanding of the relationships between body systems from the very earliest stages of embryonic development."
Cross-section of a small-spotted European river lamprey (Lampetra fluviatilis) embryo with gene staining of muscle and skin (green), bone (red), and kidney (orange). General cell staining (blue)
(Photo: Dr. Ram Reshef)
According to the researchers, one of the study's most intriguing aspects is its historical significance. As early as 1888, the German embryologist Johannes Rückert proposed that the embryonic kidney in sharks originated within the somite.
"Using modern molecular tools and advanced imaging, our study now provides evidence that Rückert identified an important developmental process more than a century ago—one that the science of his time simply lacked the means to prove," Dr. Reshef said.