For the first time, scientists have identified in mammals an essential mechanism used by amphibians to adjust to low-oxygen environments.

According to a study published today (Apr 17) in the journal Cell, the skin of mice can sense oxygen levels in the air and helps the rodents cope with oxygen-poor conditions.

While science has long-known that epidermal gas exchange is essential for amphibians, such as frogs and salamanders, and most insects, the mouse is the first vertebrate outside of amphibians to exhibit the phenomenon. "It's not part of the dogma," said Randall Johnson, the University of California, San Diego, molecular biologist who led the international team of study authors. The findings, in essence, elucidate an entirely new sensory apparatus in the mammalian response to low-oxygen environments.

Harvard Medical School professor H. Franklin Bunn, who was not involved in the study, agreed that the results were surprising. "It's very exciting," Bunn said. "It's very gratifying to me, because it brings home in spades the theme of whole-body physiology."

Johnson and his collaborators subjected two different knockout mouse lines to hypoxia, or low oxygen conditions, and observed the animals' physiological responses.

In normal mice subjected to hypoxia, a cascade of signaling pathways and hormonal secretions aid in ramping up red blood cell production so that their blood has more oxygen-carrying capacity.

Johnson and his colleagues studied two knockout mouse lines. One line carried an epidermal deletion of HIF-1α ,which upregulates the manufacture of red blood cells via erythropoietin (EPO), a hormone produced mainly in the kidneys and liver. The other carried an epidermal deletion of the von Hippel-Lindau (VHL) factor, which inhibits the action of HIF-1α. "When we knock out HIF-1α, the net result is that the animal's response to a hypoxic environment is basically blunted almost to the point of not happening," Johnson said. The VHL knockout mice overproduced EPO under hypoxic conditions. These data suggest that skin plays a heretofore unrecognized role in triggering a crucial physiological response to hypoxia in mice.

While Johnson said he and his collaborators were surprised by the findings, he added that they made sense from a molecular perspective and expected other mammals' skin to play similarly crucial roles in sensing oxygen levels. "Why would that all have vanished evolutionarily?" asked Johnson. "HIF-1α is one of the most highly conserved transcription factors in multicellular organisms."

The findings also hold therapeutic potential, the authors note, by finding a new sensory pathway that links the kidneys and liver to the production of EPO, which is currently administered to cancer patients and people with kidney disease. "From the pharmacological standpoint," Johnson said, "there could be compounds that manipulate EPO levels."