Roesner A, Hankeln T, Burmester T. Hypoxia induces a complex response of globin expression in zebrafish (Danio rerio). J Exp Biol 2006;209:2129-37.Fraser J, de Mello LV, Ward D, et al. Hypoxia-inducible myoglobin expression in nonmuscle tissues. Proc Natl Acad Sci USA 2006;103:2977-81.There have been several important milestones in biology — the first protein mutation to be discovered, the first elucidation of the crystal structure of normal and mutant proteins, the discovery of restriction fragment-linked DNA polymorphisms, the first prenatal diagnosis utilizing DNA sequence changes — stemming from the work of experimental scientists fascinated with learning from studies of human hemoglobins. After the existence of a closely functionally- and structurally-related protein, myoglobin, became apparent, we might have assumed that not much was left to be discovered. However, in 2000 Burmester and colleagues reported in Nature1 that another globin with remarkable homology to hemoglobin was present in neuronal tissues in mice and man. This ancestrally older gene was thus coined "neuroglobin." Now, Roesner, along with his colleagues at Burmester's laboratory, reports that the family of globins present in vertebrates, flies, and zebrafish has grown and that some are hypoxia-regulated. In zebrafish, there are at least six independent genes of the globin family (see Figure 1) that have evolved from a single ancestor that they shared approximately 700 million years ago. Since fish have developed a remarkable adaptability to different oxygen tensions, the role of these genes to hypoxia adaptation was investigated. In this paper, Roesner et al. report that brain neuroglobin mRNA (but not retinal neuroglobin) was dramatically up-regulated by hypoxia, while myoglobin expression was up-regulated to a lesser extent. In the second paper, Fraser and colleagues analyzed hypoxic regulation in another fish (the carp). They report widespread presence of myoglobins in unorthodox tissues such as kidneys, brain, gills, etc., and their striking regulation by hypoxia.

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Since man is not a carp, do these elegant discoveries have any meaning for humans? The functional details, such as oxygen-binding properties, the presence or absence of Bohr effects on these diverse globins, their presence in different tissues and different species2 , and the subtleties of hypoxia regulation, of these genes await elucidation. Nevertheless, there is growing evidence that the newly discovered globins are also present in mammals and found in unorthodox places such as rectal smooth muscle cells, prostate, lungs, the brain, and endocrine organs3 . Their role in oxygen delivery, protection against nitric oxide, oxygen radical toxicity, adaptation to exercise, and hypoxia is also becoming established2,3 . One can also ask if the yet-to-be-explained neurotoxicity and failure to thrive that is characteristic of type 2 congenital methemoglobinemia4  may be caused by failure to keep the heme iron in these globins in ferrous state by ubiquitous deficiency of cytochrome b5 reductase. Clearly, we will soon learn more about the importance of these newly discovered globins; hematologists will benefit from Dr. Thorsten Burmester's upcoming lecture, Neuroglobin — Fresh Blood for the Globin Family, at the Red Cell Scientific Committee session at this year's ASH meeting.

1.
Burmester T, Weich B, Reinhardt S, et al. A vertebrate globin expressed in the brain. Nature 2000;407:520-3.
2.
Hundahl C, Fago A, Dewilde S, et al. Oxygen binding properties of non- mammalian nerve globins. FEBS J 2006;273:1323-9.
3.
Riggs AF, Gorr TA. A globin in every cell? Proc Natl Acad Sci USA 2006;103:2469-70.
4.
Prchal JT and Gregg XT. Red cell enzymopathies. Hematology: Basic Principles and Practice, 4th ed. Hoffman R and Benz E (eds.), 2005.

Competing Interests

Dr. Prchal indicated no relevant conflicts of interest.