INSIGHTS | P E R S P E C T I V E S

Brain microvessels E12

moting or -inhibiting factors. Similarly, local differences in the vasculature may explain the phenomenon of OPC jumping from one vessel to another. This could be due to a set of adhesive proteins or chemotactic agents differentially expressed by the vessels. OPCs themselves may also modify the behavior of the vasculature by modulating angiogenesis and, importantly, differentiation of the blood-brain barrier. OPCs produce high amounts of Wnt7a and Wnt7b, which are major inducers of the barrier properties of the brain microcirculation (10). Although direct evidence is missing, it is conceivable that OPCs may contribute substantially to the full differentiation of the brain vasculature. At a more general level, the study of Tsai et al. introduces a novel paradigm—the role of the vasculature in guiding migratory neuroglial cells to their target area. Understanding the molecular basis of this interaction and its functional importance requires further work, but it is tempting to extend this observation to other cell types. For instance, some of the physiological mechanisms of cell-to-cell interaction described by Tsai et al. may be present during the dissemination of glioblastoma cells in the brain. These tumor cells resemble OPCs by marker expression and by their propensity to migrate over long distances, essentially eliminating any prospects for radical surgery (11). Interestingly, recent work suggests that glioblastoma cells migrate along blood vessels and disrupt the blood-brain barrier en route (12). Are the observations of Tsai et al. relevant in demyelination pathology? Although OPC migratory activity is inhibited at maturation, these precursor cells reacquire this property after pathological demyelination in the adult. This process plays a crucial role in inhibiting the onset and progression of diseases such as multiple sclerosis. It is therefore conceivable that any condition that affects OPC migration, such as local alteration or dismantling of the vasculature, may also strongly impair the capacity of the organism to repair neural injuries. ■

The Story of Comammox (COMplete AMMonia OXidiser) Wnt

OPC migration

Sdf-1 Nitrification is the term describing the conversion Cxcr4 of ammonia into nitrite and subsequently to nitrate. This process was thought to be carried out by two separate groups (e.g.Nitrosomonas & Maintenance of immature Nitrobacter) of bacteria. However, recent state discoveries shows that complete conversion of Blood-brain ammonia into nitrate could be effected by a barrier diferentiation novel genera named Nitrospira.

It plays a major role in N2 cycling

Detachment and maturation

REFERENCES AND NOTES

E18 Vascular guidance. OPCs migrate along brain microvessels to reach specific target areas. Migration is directed by increased Wnt-induced expression of the receptor Cxcr4, which binds to the chemokine Sdf-1 (embryonic mouse shown). Cross talk between endothelial cells and OPCs may influence their reciprocal functions. At arrival, OPCs detach from blood vessels and mature.

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

A. Zeisel et al., Science 347,1138 (2015). U. Funfschilling et al., Nature 485, 517 (2012). H.-H. Tsai et al., Science 351, 379 (2016). E. Lammert et al., Science 294, 564 (2008). G. Nikolova et al., Dev. Cell 10, 397 (2006). N. Kessaris et al., Nat. Neurosci. 9, 173 (2006). F. Kuhnert et al., Science 330, 985 (2010). B. Vanhollebeke et al., eLlife 8, 4 (2015). Y. Zhou et al., J. Clin. Invest. 124, 3825 (2014). J. M. Stenman et al., Science 322, 1247 (2008). G. P. Dunn et al., Genes Dev. 26, 756 (2012). S. Watkins et al., Nat. Commun. 5, 4196 (2014).

ACKNOWLEDGMENTS

E.D. and C.B. are supported by the European Research Council (268870, 294556), the Swedish Science Council, and Wallenberg Foundation. E.D. is supported by the Italian Association for Cancer Research and Telethon Foundation (GGP14149). C.B. is supported by the Leducq Foundation and Swedish Cancer Foundation. 10.1126/science.aaf1139

M I C R O B I O L O GY

The do-it-all nitrifier The discovery of bacteria that can oxidize both ammonia and nitrite upends a long-held dogma By Alyson E. Santoro

W

ith numerous amendments to the microbial nitrogen cycle over the past two decades, it seems at times that nothing is certain. Yet one aspect of the nitrogen cycle seemed clear: that the labor of nitrification—the oxidation of ammonia (NH3) to nitrite (NO2–) and ultimately nitrate (NO3–)— is divided between two separate groups of microorganisms. Sergei Winogradsky first showed this in the late 1800s when he isolated the organisms responsible for the two steps of nitrification, ammonia oxidizers and nitrite oxidizers. But a series of recent papers upends this 100-year-old dogma with the description of three different cultivated bacteria (1, 2) and an uncultivated bacterium (3) that can each carry out the complete oxidation of ammonia to nitrate. We should know by now that if a reaction is thermodynamically possible, microbes will find a way. A complete nitrifier should gain more energy per mole of substrate (1), but may grow at a slower rate, than organisms carrying out the individual steps of the pathway. Ten years ago, Costa et al. (4) modeled the trade-off between growth rate (favored by short metabolic pathways) and growth yield (favored by longer pathways). They found that this trade-off should favor the existence of a complete nitrifier when microbes grow slowly in clonal colonies. Such conditions are found in the biofilms that cover many natural and engineered surfaces. It is perhaps no surprise, then, that the complete ammonia oxidizers, or comammox bacteria, come from biofilms in an aquaculture treatment system (1), a deep subsurface pipe (2), and a bioactive filter at a drinking water treatment plant (3). In all cases, the comammox bacteria belong to the genus Nitrospira, members of which were until recently believed to rely on nitrite for growth. Horn Point Laboratory, University of Maryland Center for Environmental Science, Cambridge, MD 21613, USA. E-mail: [email protected]

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produced by the endothelium. It is unclear why the OPCs detach from the vessels in particular locations and start to differentiate. It will be interesting to learn if blood vessel factors or properties play an active role also in oligodendrocyte differentiation through, for example, changes in adhesive properties or the expression of specific differentiation-pro-

ILLUSTRATION: P. HUEY/SCIENCE

In one of the studies, van Kessel et al. (1) These discoveries contribute to a growing (11), require ammonium for biosynthesis, enriched two Nitrospira bacteria using a appreciation that nitrifiers are more than we meaning that they would have been missed bioreactor fed with a steady stream of low believed them to be (see the figure). Historiby typical strategies enriching for nitrite concentrations of ammonium. The resulting cally characterized as reliant on ammonia or oxidizers using nitrite as the sole nitrogen consortium contained the anammox (anaeronitrite for energy and inorganic carbon fixasource. Comammox bacteria and nitrite oxibic ammonium-oxidizing) bacteria Brocadia tion, both ammonia oxidizers and nitrite oxidizers may actually compete with ammonia as well as two newly discovered Nitrospira dizers have been proven by recent research to oxidizers (their previously assumed partbacteria, provisionally named “Candidatus be much more metabolically versatile. Select ners) for ammonium, highlighting a potenN. nitrosa” and “Ca. N. nitrificans.” nitrite oxidizers, such as Nitrobacter, can use tially underappreciated role for competition The genomes of the two Nitrospira species acetate or pyruvate for growth in the absence in the nitrogen cycle (12). contain the genes necessary for ammonia of nitrite. Ammonia-oxidizing thaumarchaea How does the discovery of comammox oxidation, including ammonia monooxynot only transport organic carbon sources change our perception of the global nitrogen genase (amo) and hydroxylcycle? Conventional methods Classical, two-step nitrifcation amine oxidoreductase (hao), of measuring nitrification and for nitrite oxidation, rates in the environment Ammonia oxidizers Nitrite oxidizers including the molybdoprolikely capture the activity of Nitrosomonas Nitrospira Nitrococcus tein nitrite oxidoreductase these organisms, and nitrifiNitrososphaera (nxr). Careful stable-isotope cation is already treated as Nitrosopumilus and radioisotope incubations a one-step process in many – NO2 confirmed ammonia oxidaglobal biogeochemical modNitrobacter tion and carbon fixation. els. It is uncertain, however, Using the newfound amo whether existing measureNitrospira sequences to probe public ment methods capture direct – databases, the researchers nitrification from the organic Urea, cyanate NH3 NO3 discovered an entire clade nitrogen pool. Nitrification is of putative comammox amo a major source of nitric oxide sequences previously iden(NO) and the greenhouse gas tified as particulate methnitrous oxide (N2O) to the ane monooxygenase (pmo). atmosphere; it remains to be These findings suggest that shown whether comammox Nitrospira the newly discovered bacteorganisms make either of ria were previously detected these compounds, and if so, One-step nitrifcation (comammox) in the environment but had under what conditions. Irrebeen mistakenly identified as Metabolic diversity of nitrifiers. Nitrification has long been held to be a two-step process spective of their quantitative methane-oxidizing bacteria. divided between two groups of organisms, some representatives of which are shown. Recent importance, the discovery Similarly, Daims et al. (2) studies (1–3) have uncovered nitrifiers that are capable of complete nitrification, as well as novel of comammox emphasizes enriched a thermophilic cosubstrates for the generation of ammonium. that our perception of nitrimammox bacterium, “Ca. fication (and of many other Nitrospira inopinata,” in coculture with a (5) but may even require these sources (6). biogeochemical processes) is based on physiproteobacterium. The authors sequenced Thaumarchaea may also use cyanate (7) as ological characterization of a small fraction the complete genome of Ca. N. inopinata a source of ammonia to fuel growth. Nitriteof extant microbial diversity. ■ and combined this analysis with proteomics oxidizing Nitrospira may degrade urea or REF ERENCES AND NOTES to show that both ammonia- and nitrite-oxicyanate to feed ammonia oxidizers, which in 1. M. A. H. J. van Kessel et al., Nature 10.1038/nature16459 dizing enzymes are abundant during growth. turn feed the Nitrospira with nitrite (7, 8). (2015). 2. H. Daims et al., Nature 10.1038/nature16461 (2015). They further explored whether ammoniaPerhaps the most surprising recent finding is 3. A. J. Pinto et al., mSphere 10.1128/mSphere.00054-15 oxidizing capability was lost by extant Nithat some Nitrospira grow not as nitrite oxi(2015). trospira species that are capable of nitrite dizers but as aerobic hydrogen oxidizers (9). 4. E. Costa, J. Perez, J. U. Kreft, Trends Microbiol. 14, 213 (2006). oxidation only, or whether the newly discovThe implication is that the carbon and nitro5. M. Li et al., Nat. Commun. 6, 8933 (2015). ered comammox Nitrospira acquired ammogen cycles are entwined in complex ways. 6. W. Qin et al., Proc. Natl. Acad. Sci. U.S.A. 111, 12504 (2014). 7. M. Palatinszky et al., Nature 524, 105 (2015) nia-oxidizing capability through lateral gene The approach used to uncover these com8. H. Koch et al., Proc. Natl. Acad. Sci. U.S.A. 112, 11371 (2015). transfer. Nucleotide usage in the amo gene plete nitrifiers highlights an elegant com9. H. Koch et al., Science 345, 1052 (2014). sequences is different from the rest of the bination of an old strategy—enrichment of 10. A. E. Santoro et al., Proc. Natl. Acad. Sci. U.S.A. 112, 1173 (2015). genome, suggesting acquisition of the amo microbial consortia—with the latest bioin11. D. Y. Sorokin et al., ISME J. 6, 2245 (2012). genes through a recent lateral gene transfer formatic techniques for reconstructing com12. J. L. Penn, T. S. Weber, C. A. Deutsch, American Geophysical Union Fall Meeting, San Francisco, 15 to 19 December event. plete genomes from uncultivated organisms. 2014, abstract B33I-08; http://adsabs.harvard.edu/ The newly cultivated comammox bacteThis strategy enables researchers to mimic abs/2014AGUFM.B33I..08P. ria provide support for comammox potenconditions in the environment, where both ACKNOWL EDGMENTS tial in uncultivated bacteria, such as the substrates and products are kept at low W. Haskell provided feedback on the figure. C. Deutsch provided Nitrospira genome assembled by Pinto et concentrations by other members of the early access to modeling results. A.E.S. is an associate felal. (3). As with its cultivated counterparts, consortium. It thus allows for the cultivalow in the Integrated Microbial Biodiversity program of the this genome contains genes for the transtion of novel organisms that may be missed Canadian Institute for Advanced Research and is partially supported by United States National Science Foundation award port and degradation of urea, potentially when high concentrations of substrate are OCE-1260006. providing an additional source of ammonia provided (10). Comammox Nitrospira, like for energy and biosynthesis. other recently described nitrite oxidizers 10.1126/science.aad9671 SCIENCE sciencemag.org

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