Preliminary tests on the engineered no-hypoxia-response mice suggest that they do have behavioral defects consistent with those seen in other mouse models of depression. Simon and her colleagues now are trying to determine whether inadequate hypoxia responses in the hippocampus might be at least partly to blame for depression in humans.

Some activities are known to promote neurogenesis—such as physical exercise—and here again Simon wants to know whether hypoxia signaling is a factor. “One of the things on our to-do list is to determine how exercise affects oxygen distribution in these stem-cell-rich regions of the hippocampus,” she says.

“It seems that these lower-oxygen zones are essential for maintaining neural stem cells’ healthy activity. ”

Celeste Simon

The clinical possibilities don’t end there, given the links between decreased neurogenesis and both Alzheimer’s and aging. “We haven’t yet had a chance to investigate in this area, but naturally we’re intrigued by the possibility that age-related declines in the hypoxia response help to drive the age-related functional declines we see in the brain and other organs,” says Simon.

It might seem odd that a protective response to low oxygen has ended up being adopted by some cells so that they actually need a bit of hypoxia to function normally. But most of Simon’s prior research in the field has aimed at understanding such adaptations. “Embryonic cells, for example, can grow so quickly that they create a hypoxic zone around themselves,” she says. “This switches on their hypoxia response, which among other things promotes the sprouting of new blood vessels toward them, so that they can continue to grow.” Her work has helped to show, too, how the hypoxia response is used in some cancer cells and also directly regulates stem cells in the developing bone marrow and heart.

“It’s been clear for some time now that hypoxia signaling is relevant in many areas of biology,” she says. “But it could turn out to have more importance for health and disease than we’d ever imagined.”

		From Defense to Offense Hypoxia typically triggers a defensive, “batten down the hatches” response, in which cells enter a less active, less vulnerable, non-oxygen-burning state. But in some cells, reduced oxygen levels also trigger more proactive changes designed to improve the long-term oxygen supply. When tissues are wounded and cut off from oxygen-supplying blood vessels, their surviving, oxygen-starved cells usually start producing vascular endothelial growth factor, which causes the local vascular network to sprout new vessels into the wounded tissue. Liver cells also respond to drops in ambient oxygen by producing more erythropoietin, a growth factor that stimulates the production of oxygen-carrying red blood cells. In a series of high-profile papers in the late 1990s, Simon and her colleagues showed that the same blood vessel- and blood cell-proliferation responses occur in embryos, whose fast growth routinely depletes local oxygen levels. “Hypoxia in these cases serves as a normal developmental signal,” says Simon. Over the past decade, Simon’s lab has been one of several to show that hypoxia plays a similar growth-promoting role in tumors. Even with adequate oxygen, tumors sometimes find ways to activate hypoxia-signaling pathways to spur extra blood vessel growth. Hypoxia seems to regulate the growth of tumor and other cell types more directly as well, and this is now one of the main themes of Simon’s lab. “We’ve shown that in the developing bone marrow and heart, for example, oxygen levels affect the production of key transcription factors in local stem cells, effectively regulating their state of activity,” she says. “Our most recent work extends this concept of hypoxia as a stem cell regulator to the adult brain.” – J.S.

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