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Review

Oxygen levels and the regulation of cell adhesion in the nervous system

A control point for morphogenesis in development, disease and evolution?

Kathryn L. Crossin Department of Neurobiology; The Scripps Research Institute; La Jolla, CA USACorrespondence[email protected]
Pages 49-58 | Published online: 01 Jan 2012

Abstract

In this article, I discuss the hallmarks of hypoxia in vitro and in vivo and review work showing that many types of stem cell proliferate more robustly in lowered oxygen. I then discuss recent studies showing that alterations in the levels and the types of cell and substrate adhesion molecules are a notable response to reduced O2 levels in both cultured primary neural stem cells and brain tissues in response to hypoxia in vivo. The ability of O2 levels to regulate adhesion molecule expression is linked to the Wnt signaling pathway, which can control and be controlled by adhesion events. The ability of O2 levels to influence cell adhesion also has far-reaching implications for development, ischemic trauma and neural regeneration, as well as for cancer and other diseases. Finally I discuss the possibility that the fluctuations in O2 levels known to have occurred over evolutionary time could, by influencing adhesion systems, have contributed to early symbiotic events in unicellular organisms and to the emergence of multicellularity. It is not my intention to be exhaustive in these domains, which are far from my own field of study. Rather this article is meant to provoke and stimulate thinking about molecular evolution involving O2 sensing and signaling during eras of geologic and atmospheric change that might inform modern studies on development and disease.

Elevation in Levels of the Hypoxia Inducible Factor, HIF1α, is a Hallmark of Reduced Oxygen Availability in Cell Culture and in Tissues

HIF1α is a constitutively produced protein that is normally hydroxylated by a family of prolyl hydroxylase enzymes, a modification that allows HIF to bind the von Hippel-Lindau tumor suppressor protein, targeting HIF for proteasomal degradation.Citation1-Citation4 When O2 levels are lowered, hydroxylation is reduced and degradation is prevented. The stabilized HIFα can then translocate into the nucleus and directly transactivate a number of genes to respond to hypoxia, among which are those involved in glycolysis, erythropoiesis, and angiogenesis.Citation4-Citation7 HIFs not only have direct transcriptional targets but also influence signaling systems to alter gene expression.Citation1 It is notable that HIF1α levels have been shown to be activated over a wide range of physiological O2 tensions, although the greatest increases were at levels consistent with hypoxia/ischemia in vivo.Citation8 These findings indicate that levels of HIF are functionally involved in O2 homeostasis in cells and organisms to enable the switch from aerobic to anaerobic metabolism when O2 levels are limiting. It is of interest that mice lacking HIF1α or its homolog HIF2α and their binding partner HIF1β all exhibit embryonic lethality, displaying multiple morphogenetic defects, including failure of neural tube closure.Citation9 The importance of O2 concentration on the formation of the neural folds and neural crest development was recognized in early studies of rat neural maturation in cultured embryos.Citation10

Hypoxia vs. In Situ Normoxia

The Merriam-Webster Dictionary defines hypoxia as “a deficiency of oxygen reaching the tissues of the body.” In the scientific literature, however, the word is often used to mean a level of O2 lower than that present in air, particularly in studies in vitro. Air does not reflect the in vivo environment of the majority of cell types and hence the term “in situ normoxia” has been suggested.Citation11 This novel term is meant to give a better indication what normoxia or hypoxia would be for a given cell type based on its exposure to O2 in vivo and allow cell culture to mimic more accurately the physiological state, as is beginning to be understood for neural cells.Citation12,Citation13 It also points to the importance of measurements of the levels of O2 in particular tissues in vivo. In warm-blooded organisms in vivo, such levels are critically dependent on multiple factors including vascularization and angiogenesis, levels of red blood cells and hemoglobin, cardiac capacity, as well as external oxygenation. These considerations are also critical for the interpretation of studies of “hypoxia” in cell lines that were derived in hyperoxic conditions, but later exposed to lower O2 levels.

In this regard, it is critical to emphasize two concepts that provide an outline for the sections to follow: (1) few tissues experience atmospheric levels of O2 in vivo and (2) metazoan life originated in an atmosphere considerably lower in levels of O2 than the modern atmosphere.

Cell Culture Conditions and O2 Levels

For over a decade it has been recognized that proliferation is enhanced and differentiation is altered in a number of stem cell types when cells are cultured in levels of O2 (1–8% O2) lower than those in air, previously the standard for in vitro studies (reviewed in refs. Citation12 and Citation13). Cells from the nervous system cultured under such low O2 conditions include neural progenitor cells from various brain regions,Citation14-Citation28 virally-immortalized human neural progenitor cells,Citation29 and neural crest stem cells.Citation24 Other sensitive cells are iPS cells,Citation30 embryonic stem cellsCitation22,Citation27,Citation31 and stem cells of different tissues.Citation32 These observations are consistent with what is known about O2 levels in the stem cell niches of the brain and other tissuesCitation12,Citation13,Citation16,Citation32-Citation37 and are likely to reflect more closely the native behavior of cells under physiological conditions.

A recent well-received book describes the origins of the now ubiquitous human HeLa cell line.Citation38 The author reviews the early history of cell culture, noting that the recovery of stable human cell lines was rare, an observation accounting for the extensive use of the surviving line HeLa. Indeed it is possible that many early cell cultures failed because they were grown in air, a hyperoxic environment compared with their in vivo environment. This consideration highlights the importance of taking in vivo physiological O2 tension into account when designing in vitro culture conditions.

Changes in the Expression of Multiple Types of Adhesion Molecules Accompany the Growth of Neural Stem Cells in Reduced O2 Atmospheres In Vitro

Cell adhesion between and among cells is a critical component of morphoregulation during development and in disease.Citation39,Citation40 Molecules of the immunoglobulin and cadherin families of cell adhesion molecules (CAMs) link cells together and collectively play major roles in the formation of tissues and organs. In addition, molecules in the extracellular matrix (ECM) surrounding cells, along with integrins and other ECM receptors on the cell surface, are critical for cell migration.

Several recent studies have linked the altered expression of cell and extracellular matrix adhesion molecules and matrix modifying enzymes to growth of neural stem cells in culture in a reduced O2 environment.Citation23,Citation41 Moreover, studies from my laboratory found that the levels of mRNAs for several CAMs, ECM proteins, and ECM modifying enzymes differed in rat embryonic neural stem cells cultured for 72 h in 1% vs. 20% O2.Citation23 Another study evaluated 5704 genes in rat neural stem cells and found that, of all the genes whose expression differed between cells cultured at 3% or 20% O2 for 24 h, a significant fraction were involved in cell adhesion or migration.Citation41

Adhesion molecule expression in vitro was also altered in several other cell types exposed to reduced O2 levels, including mesenchymal stem cells,Citation42-Citation44 hematopoietic stem cellsCitation45 and a melanoma cell line.Citation44

Connection between Oxygen Levels, HIF1α, Wnt Signaling and Adhesion Molecule Expression Suggests One Mechanism to Control Neural Stem Cell Proliferation

A significant finding in two recent papers is the connection between HIF1α stabilization and the activation of the Wnt pathway by lowered O2.Citation22,Citation23 As reported in many systems, activation of HIF-1α occurred in rat embryonic neural stem cells cultured in lowered O2.Citation22,Citation23 As described above, stabilization of the levels of the HIF1α protein is a hallmark of hypoxia,Citation2,Citation12,Citation13,Citation46,Citation47 but HIF1α levels are also known to vary significantly under different physiological levels of O2.Citation8

Our studyCitation23 also showed that a critical downstream target of Wnt was an increased expression of matrix metalloproteinase 9 (MMP9), an ECM modifying enzyme. MMP9 expression had previously been shown to be upregulated by Wnt activation in human lymphocytes.Citation48 More importantly, we showed that the increase in the level and activity of MMP9 was essential for the increased proliferation and migration of embryonic rat neural stem cells at reduced levels of O2.Citation23 Hence modifications to the ECM can control neural stem cell proliferation in vitro and may do so in vivo in the stem cell niche. Evaluating the proliferation and migration of neural stem cells in the MMP9 knockout mouse will be revealing and an assessment of the critical enzyme targets of MMP9 should be facilitated using this model.

Wnt is a critical regulator of cell adhesion in multiple cell types via its ability to alter β-catenin activity, the so-called canonical Wnt signaling pathway.Citation49-Citation51 Canonical Wnt signaling primarily influences cadherin-mediated adhesion, subcellular localization, and effects on cell junctions.Citation52-Citation56 The non-canonical, planar cell polarity Wnt pathwayCitation57 involves cell rearrangements and migration during development, particularly those in the nervous system.Citation58 These pathways involve extensive changes in cell adhesion and in the cytoskeleton.Citation57

Another mechanism by which O2 levels could affect adhesion systems is via the engagement of microRNAs, many of which target various adhesion molecule mRNAs and are known to change dramatically under hypoxic conditions.Citation59-Citation65 Thus O2 influences Wnt activity via HIF1α activation, and Wnt in turn can influence multiple adhesive systems directly or indirectly. Such adhesive interactions are clearly a substrate for the evolution of multicellular organisms over geological time.Citation57,Citation66,Citation67

Hypoxia in Early Embryonic Development

Studies of mammalian placental development were among the first to recognize the importance of O2 tension for proper development, both of the early placenta and later of the first trimester human embryo, prior to the complete establishment of maternal-fetal circulation.Citation68-Citation70 The hypoxic environment in utero has been postulated to play a key role in trophoblast proliferation and invasion, in both in vivo and in vitro studies.Citation68,Citation70 In this system, low O2 promotes the expression of several extracellular matrix adhesion molecules, such as those of the β1 integrin family as well as matrix modifying enzymes such as uPA and MMP-2, which play essential roles in trophoblast invasion (reviewed in ref. Citation68) This process is an essential initial mechanism for formation of the placenta, and aberrations in these early events can have serious consequences for placental function resulting in adverse pregnancy outcomes.Citation69,Citation70

Influence of Hypoxia-Ischemia on Adhesion Molecule Expression in the Fetal and Adult Brain

Hypoxia in utero is a key factor contributing to impaired neural development. In a mouse model of fetal hypoxia, neuronal migration was increased in the CA1 and dentate gyrus regions of the hippocampus along with biphasic changes in molecules that influence migration, including reelin, disabled and APP.Citation71 Using the hypoxia indicator pimonidazole, it was revealed that hypoxic areas colocalized with HIF1α expression and with the adhesion molecule PE-CAM, a marker of endothelial cells, indicating that hypoxia promotes the proliferation and migration of these cells to stimulate angiogenesis during brain development.Citation72

Studies of cerebral hypoxia in adult animals induced either by middle cerebral artery occlusion (stroke model) or by hypobaric O2 exposure (chronic hypoxia) demonstrated changes in multiple adhesion systems. For example, in microvessel-rich regions isolated from stroke-affected human brains by laser-capture microdissection, proangiogenic adhesion molecules were upregulated, including NR-CAM, MMP-2, TIMP-1 and β-catenin.Citation73 In a mouse stroke model, V-CAM, laminin, dystroglycan and α6 integrin were upregulated and the number of proliferative endothelial cells were increased suggesting that these molecules contribute to angiogenesis in response to cerebral ischemia.Citation74 In chronic cerebral ischemia, fibronectin was increased as was the expression of integrin α5β1 on endothelial cells.Citation75 Subsequently, changes in astrocytes occurred, including increases in α6β4 integrin and dystroclycan, presumably contributing to the cell interactions necessary for the formation of astrocytic end feet to support the restoration of a mature brain endothelium.Citation75 It is known that cerebral edema occurs after a hypoxic incident due to a compromised blood-brain barrier and the resultant increase in cerebrovascular permeability. In an in vitro model of the blood-brain barrier subjected to hypoxia, levels of expression of the E-cadherin adhesion molecule were decreased; this molecule is known to be important for blood-brain barrier function.Citation76

Adhesion Molecule Expression in Neural Stem Cells Favors Their Incorporation into Regenerating Tissues after Various Lesions to the CNS

Early studies revealed that the polysialylated form of N-CAM (PSA-N-CAM) was prominently expressed in neural stem cells migrating in the rostral migratory stream from the SVZ to the olfactory bulb.Citation77 Subsequent studies showed that loss of PSA or N-CAM decreased the normal migration of these cellsCitation78,Citation79 and allowed their increased migration into demyelinating lesionsCitation80,Citation81 or facilitated myelination when transplanted into lesioned spinal cord.Citation82 A recent study indicates that increased expression of reelin helps to facilitate migration of cells from the rostral migratory stream into demyelinating lesions in the corpus callosum.Citation83

Other studies have indicated that overexpression of the L1 neural cell adhesion molecule in mouse embryonic stem (ES) cells supported the regrowth of corticospinal axons and promoted functional recovery after spinal cord compression injury.Citation84,Citation85 The same L1-ES cells promoted recovery from excitotoxic lesions to the mouse striatum.Citation86 Expression of the extracellular matrix proteins thrombospondin 1 and 2 were correlated with a positive recovery of neuronal function after transient ischemia.Citation87

An interesting study relevant to the use of stem cells to promote recovery after stroke used cells selected for adhesion molecule expression.Citation88 Mouse neural stem cells were selected for expression of the integrin CD49d, which is a receptor for V-CAM in endothelial cells. These selected cells showed enhanced homing toward a hypoxic lesion and enhanced behavioral recovery in a mouse stroke model. The authors postulate that these effects are due to better transmigration through the vascular endothelium.

All of the foregoing perturbations to stem cells and their environments should be of great value for studies aimed at promoting regeneration by mimicking the mechanical forces that bias stem cell fate.Citation89 Alterations of adhesion molecule expression in the endothelial environment, in addition to influencing tumor vascularization and O2 delivery, can serve to generate signals for neighboring neural stem cells to proliferate and differentiate.Citation90,Citation91

Hypoxia and the Adhesive Glioma Cell Microenvironment

Glioma cells bear many striking resemblances to neural stem cells.Citation92-Citation95 These tumors are thought to arise when neural stem cells at specific stages of development either undergo mutation or respond to environmental signals and become immortalized. Like all solid tumors, gliomas show large areas of hypoxia and it has been suggested that hypoxia favors the proliferation and stabilization of cancer stem cells, which can maintain tumor propagationCitation13,Citation85,Citation93,Citation94,Citation96,Citation97 In glioma cells, the effects of “hypoxia,” or low O2 in situ, are similar to that of a low O2 niche in normal neural stem cells.Citation12,Citation13

HIFs are commonly expressed in gliomas and HIF1 blockade inhibited migration and invasion of malignant glioma.Citation92 At least in part of the decreased migration was due to the downregulation of MMPs 2 and 9. MMP-13 is expressed specifically in glioma stem cells and its inhibition also results in decreased glioma stem cell migration and invasion.Citation98 It has also been postulated that hypoxia increases the strength of cell-cell adhesion in glioma cells in culture.Citation99

Glioma stem cells have been shown to express the L1-CAM, which is implicated in increased invasiveness and metastasis.Citation98,Citation100 Expression of this adhesion molecule is correlated with poor outcome in patients.Citation100 In vitro, decreasing the levels of L1 inhibited cell growth and neurosphere formation and decreased apoptosis.Citation98 The Wnt signaling pathway, many downstream targets of which are adhesion molecules,Citation53-Citation55 has recently been shown to influence glioma tumorigenesis.Citation101

It is well established that the turnover of cell and matrix adhesions is essential to allow for epithelial mesenchymal transformation and support tumor migration and invasion into surrounding tissues.Citation85,Citation93,Citation97,Citation102 Targeting of these molecules has provided several avenues for developmental therapeutics,Citation93,Citation95,Citation97,Citation98 although the similarities between glioma cells and neural stem cells present difficulties in identifying targeted therapeutics that do not affect endogenous normal cells.Citation93,Citation95,Citation97,Citation98

HIFs and Hypoxia at the Organismal Level

Genetic variations in HIFs have been seen in human and animal populations dwelling at high altitudes,Citation103-Citation108 in Drosophila that have been adapted to low O2 levelsCitation109,Citation110 and in blind mole rats that live in hypoxic underground burrows.Citation111,Citation112 Thus modern organisms have adapted and are capable of adapting to alterations in the O2 environment via HIF1 changes and alterations in genes involved in aerobic metabolism. It is not surprising that HIF mutations and HIF dysregulation are associated with multiple diseasese.Citation171 As outlined in the final sections, it is tempting to speculate that cell adhesion events influenced by increasing O2 levels in the early earth atmosphere provided the critical control of cell and/or substrate adhesion that favored the emergence of multicellularity during evolutionary time.

Organismal Evolution Occurred at Vastly Lower O2 Levels than Those in the Present Atmosphere

Biologists think about molecular, cellular and organismal evolution, but we seldom consider them in light of geologic and atmospheric change. Integration of this key element in the evolution of life on earth could encourage new ways of thinking about molecular and organismal evolution. Many of us were not trained in earth and atmospheric sciences or even cognizant that such issues might play a key role in the development of life on earth, notwithstanding perhaps metabolic biochemists, who necessarily think about aerobic and anaerobic cellular energy production (e.g., refs. Citation5, Citation113 and Citation114). Indeed this point serves as a reminder that mitochondria, the key players in aerobic metabolism, are central to many aspects of development and evolution (see below). The evolution of metabolic processesCitation114,Citation115 played a critical role and continues to do so, especially in high energy-requiring tissues such as the nervous, cardiac, and muscular systems.

When unicellular organisms first appeared on earth, more than three billion years ago,Citation116 the Earth's atmosphere and oceans were anoxic (see ).Citation117 Around 2.5–3 billion years ago, photosynthesizing cyanobacteria evolved and began producing O2, which initially was absorbed by minerals but, exhausting this sink, eventually accumulated in the atmosphere, resulting in the Great Oxygenation Event.Citation117 This event is believed to have caused the extinction of a large number of organisms that were poisoned by toxic O2 levels.Citation116 Eukaryotes and archaebacteria appeared about two billion years ago during the Neoproterozoic period as O2 levels were rising, albeit still considerably lower than modern levels.Citation117,Citation118 Multicellular life probably arose 1–1.5 billion years ago and bilaterian animals were prevalent 500 million years ago just before the Cambrian explosion.Citation116,Citation119

These topics are complex and have been given short shrift by my exclusive focus on O2 levels. For example, a recent study indicated that as late as the Devonian era, O2 levels were lower than the present and impacted the emergence of larger vertebrates with high metabolic rates, e.g., predatory fish.Citation119 Ocean oxygenation appears to have acted (and appears to be doing so still) as an “evolutionary barrier” to the increasing size of predatory fish.Citation119,Citation120 In a similar vein, a recent paper postulates that variations in O2 levels acted to select among arthropods during the Cambrian ages, with the most successful species being those that were tolerant of, and had the ability to respond adaptively to, changes in O2 levels in seawater.Citation121 Consideration of O2 levels as drivers of evolution is still being intensely debated in studies of both modern evolution and marine ecology, increasingly so as ongoing data emerge from measurements of O2 levels both in geological samplesCitation117-Citation119,Citation122 and in regions of present-day oceans that have become hypoxic due to the influences of climate change.Citation123

Phylogeny of Some Oxygen Binding and Sensing Molecules

It is of interest that homologs of the globins, molecules that bind O2 via heme coordination, are found in modern prokaryotes.Citation124-Citation128 Perhaps such O2-carrying proteins evolved to capture the very small amounts of molecular O2 generated in early cellular life to be used for critical oxidation reactions such as tyrosine synthesis, hydroxylation of amino acids, and, in eukaryotes, sterol biosynthesisCitation129 and the hydroxylation of HIF1α.Citation2 Yet a scan of the current GenBank database indicates that the hypoxia responsive protein, HIF1α, is found only in eukaryotes. Homologs of the von Hippel-Lindau protein, which controls HIF degradation,Citation3,Citation4,Citation118 are found in Volvox.Citation130 Volvox is a spherical, sponge-like member of the green algae with a small number of specialized cell types, including germ cells.Citation67,Citation131 Of all extant organisms, Volvox is thought to be the best model system for understanding the emergence of the earliest multicellular organisms as they evolved from unicellular ancestors.Citation67,Citation131

Adhesion Molecules, Oxygen Levels, Prokaryotic Symbiosis and Multicellularity

The last universal common ancestor for all extant life was a prokaryote that had ribosomes and a plethora of redox proteins, but no organelles such as chloroplasts or mitochondria.Citation132-Citation136 The appearance of modern cellular organelles, including mitochondria and chloroplasts, and possibly cilia and flagella, almost certainly came about as a result of the symbiotic fusion of individual free-living unicellular organisms early in cellular evolution.Citation137-Citation139 Although famously championed by Lynn Margulis,Citation137 these ideas were suggested earlier by several authors.Citation115 Creation of such symbionts would likely be facilitated by adhesive mechanisms between cells. Support for an adhesive mechanism for symbiosis has been strengthened by the description of “predatory prokaryotes.”Citation140 These bacteria adhere to the surfaces of other bacteria allowing their entry into the host cell. Clearly molecular mechanisms for adhesivity, possibly driven by the induction of gene expression by increasing O2 during evolutionary time, might have facilitated such interactions.

Notably many transcription factors, in addition to HIF1α, are known to be sensitive to cellular redox state (which is influenced by, but not restricted to, alterations in O2 availability).Citation141-Citation144 Targets of these factors would increase the number of molecular changes that might increase in responsiveness to altered O2 concentrations in addition to the changes in adhesion molecules emphasized here.

The appearance of multicellularity also necessitated a mechanism for cell-to-cell and cell-to-substrate adhesion, which arose by diverse pathways in various lineages.Citation66,Citation67 As noted above, the volvocine algae are the extant organisms thought to most closely resemble the earliest multicellular organisms in evolution.Citation67 Volvox has a cell adhesion molecule homologous to fasciclin I in DrosophilaCitation145 as well as a sulfated glycoprotein that appears at a distinct phase of embryogenesis when it might facilitate cell interactions,Citation146,Citation147 such as those that form cytoplasmic bridges in the Volvox embryo.Citation148 A large number of extracellular matrix molecules in Volvox has been described biochemicallyCitation149,Citation150 and genomically.Citation130 Several distinct types of ECM zones have been observed ultrastructurally.Citation149 Moreover, ECM assembly has been shown to be inhibited by sulfhydryl reagents,Citation151 indicating sensitivity to the local redox environment. Thus molecules for cell and extracellular matrix adhesion exist and certainly play a critical role in this primitive multicellular organism.Citation57,Citation66,Citation67

Other organisms have been used in modern studies to mimic processes that supported the emergence of multicellularity. One is D. discoideum, a single-cell amoeboid organism that forms aggregates and subsequent fruiting bodies upon starvation. The process of aggregation is guided by the differential distribution of several cell and extracellular adhesion molecules.Citation152-Citation155 The genome of D. discoideum contains homologs to several families of adhesive proteins.Citation156 Indeed, the formation of epithelial structures during morphogenesis requires homologs of both α- and β-catenin, suggesting that these junctional and signaling proteins predated the appearance of metazoans.Citation157 In the case of multicellular colony formation in the single cell choanoflagellate, S. rosetta, colonies formed through cell division and not by the aggregation of individual cells.Citation158 Nevertheless, in both model organisms and the evolution of multicellularity, post-division adhesive mechanisms must have been operative to hold cells together, whether by direct cell adhesion or encasement within a common extracellular matrix, similar to what occurs in Volvox. A recent study that selected for aggregates in S. cerevisiae over several generations demonstrated that multicellularity could occur rapidly and provided another example of post-division colony formation.Citation159 Any of these model systems could be amenable to test whether exposure to O2 levels comparable to those that occurred during the emergence of multicellular organisms influences the expression of any of the known adhesion molecules in the respective systems. Such experiments would also be a good test of the extent of generality in the evolution of cell adhesion mechanisms.Citation66,Citation153

While it is not novel to suggest that various kinds of adhesion events were necessary for the emergence of multicellularity,Citation57,Citation66,Citation67 the recent studies described here raise the intriguing possibility that the increasing (and at times decreasing)Citation117,Citation160 O2 levels over evolutionary time might have exerted a strong selective influence on the evolution and production of adhesion molecule precursors.

Summary and Additional Considerations

Low atmospheric O2 concentrations, at levels that are now commonly referred to as “hypoxia,” were the norm during the evolution of multicellular organisms. It is possible that alterations in O2 levels drove the emergence and expression of molecules that supported adhesion thus facilitating prokaryotic symbiosis and multicellularity. HIF1 and its hydroxylating (PHD-family) enzymes probably did not evolve to deal with “hypoxia” but more likely acted as O2 sensors (as has been suggested for PHDCitation2,Citation161) in order to regulate the response of suites of genes to the local and atmospheric O2 environment over evolutionary time.Citation47,Citation162,Citation163 Consideration of the evolutionary origins of O2-responsive molecular mechanisms might greatly broaden our understanding of how such molecules function in development, especially in stem cell niches. For example, particular levels of O2 could select for suites of adhesion molecules that would select among and guide the processes of cell proliferation, migration, and differentiation. For example, altered adhesive mechanisms brought about by differing O2 levels may occur when stem cells leave the proliferative niche and migrate and differentiate in adjacent tissues. Such an idea is consistent with the observation that neural stem cells proliferate (and possibly switch between activity and quiescence) in the lowest O2 levels (reviewed in refs. Citation12 and Citation13) and that increased O2 levels support stem cell differentiation into particular lineages.Citation13

In addition to understanding diseases and development of the central nervous system,Citation13,Citation164 these issues are also useful in considering the consequences of hypoxia in tissues and the progression of diseases in which cellular niches low in O2 are thought to influence cell behavior, particularly cancerCitation165-Citation168 and other diseases of proliferative misregulation, such as inflammation, fibrosis and sclerosis.Citation169

Figure 1. Key events in biological evolution superimposed on the range of oxygen levels in the earth's atmosphere. The figure was modified from reference Citation117 with the author's permission. More recent data indicate a transient rise in levels (of 0.04–0.1 pO2) between 2.0 and 2.4 billion years before the present.Citation160 The biological evolutionary times are compiled from several references and citations within.Citation116,Citation117,Citation170 The geological times have wide variances and change as new data and models accumulate.

Figure 1. Key events in biological evolution superimposed on the range of oxygen levels in the earth's atmosphere. The figure was modified from reference Citation117 with the author's permission. More recent data indicate a transient rise in levels (of 0.04–0.1 pO2) between 2.0 and 2.4 billion years before the present.Citation160 The biological evolutionary times are compiled from several references and citations within.Citation116,Citation117,Citation170 The geological times have wide variances and change as new data and models accumulate.

Acknowledgments

I thank Drs Gerald Edelman, David Edelman, Vincent Mauro, Joseph Gally and Bruce Cunningham for helpful discussions and for their critical reading of the manuscript. I also thank Dr Sigeng Chen for introducing me to the topic of changes in oxygen levels during geologic evolution. Thanks to Dr David Edelman for figure preparation. Work in the author's laboratory is supported by the Scripps Research Institute Department of Neurobiology, the Mathers Foundation and Promosome, L.L.P. There are no conflicts of interest.

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