Defining the NG2-expressing cell of the adult CNS

The NG2 proteoglycan is believed to be an in vivomarker for oligodendrocyte progenitors found in the developing brain. The prevalence of NG2-expressing cells that remain in the adult CNS following the end of gliogenesis is significant. Current research is focused on how this cell participates in the normal function of the adult CNS and whether it may be activated by injury and/or contribute to repair. Despite substantial evidence for a sub-population of NG2-expressing cells playing a glial progenitor role in the adult CNS, there is much to be learned. Specifically, the heterogeneity of this population has not been adequately addressed for the adult CNS and while NG2 cells continue to divide in the adult CNS it is not clear what function they serve once myelination is complete. Future studies should elucidate the functional importance of NG2 in a variety of cell functions and shed light on the role NG2-expressing cells play in the intact and diseasedCNS.     

Foraging Ontogeny is not Linked to Delayed Maturation in Squirrel Monkeys (Saimiri sciureus)

The acquisition of complex foraging behaviors by young is a proposed cause of a prolonged juvenile phase in many vertebrates, including primates. I compared the foraging behaviors of infant, juvenile and adult squirrel monkeys to determine if significant age‐related differences in foraging behavior and efficiency were present. Infants and juveniles differed from each other in patterns of prey and fruit foraging, but few differences existed between juveniles and adults. Despite differing in the use of foraging substrates, young juveniles (8–12 mo) were as efficient as older juveniles (1–4 yr) and adults at capturing and processing large prey. Young juveniles (<1 yr) were limited in their ability to consume husked palm fruits due to an inability to peel them to obtain pulp. By 1 yr of age, however, foraging behaviors of adults and juveniles were nearly indistinguishable. The absence of meaningful differences between adults and juvenile foraging is not consistent with the hypothesis that the need to develop foraging skills accounts for the pattern of extended juvenility in squirrel monkeys.     

Heterogeneity of NG2-expressing cells in the newborn mouse cerebellum

The function and origin of NG2+ cells in the adult brain are still controversial. A large amount of data is available which strongly indicates that adult NG2-expressing cells form a heterogeneous population, constituted by oligodendrocyte precursor cells (OPCs) and a fourth novel type of glial cells named the synantocytes. Whether these two populations derive from the progressive maturation of perinatal NG2+ OPCs or are generated as separate populations is not known. We used organotypic cultures of newborn mouse cerebellum depleted, by anti-mitotic drug treatment, of their NG2+ cells with perinatal features (high proliferating rate and high oligodendrocytic differentiation ability). In these cultures, despite the lack of myelin after 14 days in vitro, numerous NG2+ cells remained. We show that these BrdU-resistant cells were able to slowly divide, as adult NG2+ cells do. Although many of these cells expressed O4, only a very small fraction of them was further engaged in oligodendrocyte lineage, as they had an extremely poor capacity to generate myelin sheaths to the Purkinje cell axons. These results support the view that at least two distinct populations of NG2+ cells coexist in the cerebellum from birth: one with the young OPC characteristics, another with adult NG2+ cell characteristics. Thus, a fraction of adult NG2+ cells do not derive from the maturation of perinatal OPCs.     

Effects of age and sex on intra-group spacing behaviour in juvenile savannah baboons,Papio cynocephalus cynocephalus

Twenty juvenile members of known genealogies in two baboon groups were studied over a 16-month period to evaluate a number of predictions about juvenile spacing behaviour based on the natural history of savannah baboons. Young juveniles (1–2·5 years old) approached more frequently and spent more time in proximity to other group members than did old juveniles (3–5·5 years old). In particular, young juveniles associated more closely with their mothers, particular adult males (possible fathers) and age-peers than did old juveniles. Approaches of young juveniles towards unrelated, high-ranking adults were more likely to occur during feeding than were those of old juveniles. Also, following such an approach, young juveniles were more likely than old juveniles to begin feeding immediately. The overall rates of feeding of old juveniles were depressed when they were in proximity to unrelated, high-ranking adults, whereas the feeding rates of young juveniles were not. Juvenile males approached adult males more often than did juvenile females. Juvenile females approached unrelated adult females more often than did juvenile males. Sex differences also existed in juveniles' choices of unrelated adult female neighbours. Juvenile females associated most often with lactating females, whereas juvenile males associated primarily with cycling females. During group resting, juvenile females approached adult females from higher-ranking matrilines more often than they approached adult females from lower-ranking matrilines. Juvenile males did not exhibit this attraction. Also, among old juveniles, females associated closely with their mothers, whereas males did not. Taken together, the results support the hypotheses that juvenile baboons associate with group members in ways that (1) enhance the probability of surviving an early period of high mortality, (2) create opportunities for social learning of sex-typical behaviours/skills, and, for females, (3) facilitate acquisition of familial dominance status.     

NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration

The mammalian CNS contains a ubiquitous population of glial progenitors known as NG2+ cells that have the ability to develop into oligodendrocytes and undergo dramatic changes in response to injury and demyelination. Although it has been reported that NG2+ cells are multipotent, their fate in health and disease remains controversial. Here, we generated PDGFαR-CreER transgenic mice and followed their fate in vivo in the developing and adult CNS. These studies revealed that NG2+ cells in the postnatal CNS generate myelinating oligodendrocytes, but not astrocytes or neurons. In regions of neurodegeneration in the spinal cord of ALS mice, NG2+ cells exhibited enhanced proliferation and accelerated differentiation into oligodendrocytes but remained committed to the oligodendrocyte lineage. These results indicate that NG2+ cells in the normal CNS are oligodendrocyte precursors with restricted lineage potential and that cell loss and gliosis are not sufficient to alter the lineage potential of these progenitors.     

Role of the cellular prion protein in oligodendrocyte precursor cell proliferation and differentiation in the developing and adult mouse CNS

There are numerous studies describing the signaling mechanisms that mediate oligodendrocyte precursor cell (OPC) proliferation and differentiation, although the contribution of the cellular prion protein (PrP(c)) to this process remains unclear. PrP(c) is a glycosyl-phosphatidylinositol (GPI)-anchored glycoprotein involved in diverse cellular processes during the development and maturation of the mammalian central nervous system (CNS). Here we describe how PrP(c) influences oligodendrocyte proliferation in the developing and adult CNS. OPCs that lack PrP(c) proliferate more vigorously at the expense of a delay in differentiation, which correlates with changes in the expression of oligodendrocyte lineage markers. In addition, numerous NG2-positive cells were observed in cortical regions of adult PrP(c) knockout mice, although no significant changes in myelination can be seen, probably due to the death of surplus cells.     

NG2-expressing cells in the nervous system revealed by the NG2-EYFP-knockin mouse

The NG2 glycoprotein is a type I membrane protein expressed by immature cells in the developing and adult mouse. NG2+ cells of the embryonic and adult brain have been principally viewed as oligodendrocyte precursor cells but have additionally been considered a fourth glial class. They are likely to be a heterogeneous population. In order to facilitate studies on the function of NG2+ cells and to characterize these cells in situ, we generated an enhanced yellow fluorescent protein (EYFP) "knockin mouse." EYFP-expressing cells in heterozygous knockin mice expressed the NG2 protein in all regions and at all ages studied. The EYFP+ cells did not express markers of mature glia, developing or mature neurons or microglia, but expressed markers typical for immature oligodendrocyte-lineage cells. Examination of the hippocampus showed heterogeneity in the population with regard to expression of S100ss and glutamine synthetase. Furthermore, different subpopulations of NG2+ cells in the hippocampus could be recognized by their electrophysiological properties.     

Interaction of syntenin-1 and the NG2 proteoglycan in migratory oligodendrocyte precursor cells

Migration of oligodendrocyte precursors along axons is a necessary prerequisite for myelination, but little is known about underlying mechanisms. NG2 is a large membrane proteoglycan implicated in oligodendrocyte migration. Here we show that a PDZ domain protein termed syntenin-1 interacts with NG2 and that syntenin-1 is necessary for normal rates of migration. The association of syntenin-1 with NG2, identified in a yeast two-hybrid screen, was confirmed by colocalization of both proteins within processes of oligodendroglial precursor cells and by coimmunoprecipitation from cell extracts. Syntenin-1 also colocalizes with NG2 in "co-capping" assays, demonstrating a lateral association of both proteins in live oligodendrocytes. RNA interference-mediated down-regulation of syntenin-1 in glial cells results in a significant reduction of migration in vitro, as does the presence of polyclonal antibody against NG2. Thus syntenin plays a role in the migration of oligodendroglial precursors, and we suggest that NG2-syntenin-1 interactions contribute to this.     

Recruiting juvenile damselfish: the process of recruiting into adult colonies in the damselfish Stegastes nigricans

Juveniles of Stegastes nigricans occur in adult colonies, solitarily, and occasionally in juvenile colonies. We concentrated on solitary juveniles and those in adult colonies. We examined the costs and benefits of different settlement strategies, quantified the territory requirements of adults, and investigated the process of how juveniles make the transition to adult territorial fish. An adequate adult territory lies next to those of other adults, is proportional in area to the size of the adult, and contains a refuge tunnel whose entrance is sufficiently large. Compared with solitary juveniles, those <4 cm total length inhabiting adult colonies experienced reduced heterospecific competition for algal food and consequently benefited from a greater density of algae. A cost of recruiting into an adult colony, however, was increased attacks by adults. Juveniles that settled in adult colonies avoided attacks by retreating into small holes inaccessible to adults. As juveniles in adult colonies grew, they were chased less often by adults, whereas they themselves chased adults and heterospecific fish more often. Because territory size correlated with fish size in adult colonies, its area had to expand as the young fish grew, and that expansion was done at the expense of neighbors. Obtaining the space needed by an adult may be possible only when the juvenile settles directly into an adult colony. Juveniles that first settle down solitarily, or in juvenile colonies, may later attempt to enter adult colonies. However, because they do so as larger juveniles, they would have difficulty insinuating themselves into small refuges, which is essential for retreat from the adults. Received in revised form: 4 January 2001 Electronic Publication     

Opening the Social Gateway: Early Vocal and Social Sensitivities in Brown-Headed Cowbirds (Molothrus ater)

The organization of cowbird ( Molothrus ater ) social groups affords individuals living in the groups different opportunities for learning and also structures trajectories of social development. Here, we studied the influence of adults on social organization of very young cowbirds. In three experiments, we housed juvenile birds in large, seminatural environments that either contained or did not contain adult conspecifics. We then observed the social associations and vocalizations of juveniles in each environment. The presence of adults in the social environment influenced the assortment and singing patterns of juveniles, although throughout the three experiments adults rarely interacted physically with juveniles. Juveniles housed with adults interacted with other juveniles more often and sang significantly less often than juveniles housed without adults. Effects of adult presence or absence on social organization and singing patterns emerged extremely rapidly and could be reversed quickly. Taken as a whole, the experiments revealed that very young cowbirds, in the first days of independence from their hosts, were sensitive to, and reacted rapidly to, the composition of their social environment. Specifically, presence of other age classes of individuals within the group increased juvenile associations and delayed production of vocalizations by juvenile males. Self-organization within the social group produced different social environments, which could in turn create different gateways for social learning and vocal development.     

The Role of NG2 Proteoglycan in Glioma

Neuron glia antigen-2 ((NG2), also known as chondroitin sulphate proteoglycan 4, or melanoma-associated chondroitin sulfate proteoglycan) is a type-1 membrane protein expressed by many central nervous system (CNS) cells during development and differentiation and plays a critical role in proliferation and angiogenesis. ‘NG2’ often references either the protein itself or the highly proliferative and undifferentiated glial cells expressing high levels of NG2 protein. NG2 glia represent the fourth major type of neuroglia in the mammalian nervous system and are classified as oligodendrocyte progenitor cells by virtue of their committed oligodendrocyte generation in developing and adult brain. Here, we discuss NG2 glial cells as well as NG2 protein and its expression and role with regards to CNS neoplasms as well as its potential as a therapeutic target for treating childhood CNS cancers.     

The Influence of Social Environment: Behavior of Unrelated Adults Affects Future Juvenile Behaviors

Juveniles' behaviors are often influenced by the behaviors of conspecifics. Most experimental studies of the influence of conspecific behavior vary the social environment by the presence or absence of conspecifics or investigate the impact of the outcome of social encounters (winner/loser effects) but less frequently expose individuals to variation in behavioral phenotypes present in the social environment. Based on previous work showing that juveniles of the salamander Plethodon cinereus are likely to interact frequently with non‐parental adults, I hypothesized that territorial adults in the social environment alter the future behaviors of juveniles. I measured the intracohort social behaviors of juvenile salamanders collected from two geographic areas, Michigan (MI) and Virginia (VA), before and after housing with ostensibly territorial (VA) or non‐territorial (MI) adults. There were overall effects of adult territoriality and aggression on the behavior of juveniles. However, juveniles from populations in MI were especially susceptible to behavioral modification. Compared with behaviors prior to being housed with adults, MI juveniles increased investigatory and escape behaviors in juvenile–juvenile interactions after being housed with adults that displayed territorial behaviors and decreased investigatory and escape behaviors after being housed with non‐territorial adults. This study shows that not only is a specific behavior, territoriality of adult salamanders, a social environment that modifies future juvenile behaviors, but the effects of social environment may differ between populations.     

NG2 cells in the brain: a novel glial cell population.

There exists a significantly large population of glial cells in the mammalian central nervous system (CNS) that can be identified by the expression of the NG2 proteoglycan. Cells that express NG2 (NG2 cells) are found in the developing and mature CNS and are distinct from neurons, astrocytes, microglia, and mature oligodendrocytes. They are often referred to as oligodendrocyte progenitor cells because of their ability to differentiate into oligodendrocytes in culture. However, the observation that a large number of NG2 cells persist uniformly and ubiquitously in the adult CNS and display a differentiated morphology is not entirely consistent with the notion that NG2 cells are all oligodendrocyte progenitor cells. The role of NG2 cells in oligodendrocyte regeneration and their non-progenitor role in the mature CNS are discussed in this review.     

Variation in Helper Type Affects Group Stability and Reproductive Decisions in a Cooperative Breeder

Recent studies have shown that differences in life history may lead to consistent inter‐individual variation in behavioural traits, so‐called behavioural syndromes, animal personalities or temperaments. Consistencies of behaviours and behavioural syndromes have mainly been studied in non‐cooperative species. Insights on the evolution of cooperation could be gained from studying individual differences in life histories and behavioural traits. Kin selection theory predicts that if an individual’s reproductive ability is low, it had to aim at gaining inclusive fitness benefits by helping others. We tested this prediction in the cooperatively breeding cichlid Neolamprologus pulcher, by assessing reproductive parameters of adults that had been tested earlier for aggressiveness and for their propensity to assist breeders when they had been young (‘juveniles’). We found that juvenile aggression levels predicted the acceptance of a subordinate in the group when adult. Males which were aggressive as juveniles were significantly more likely to tolerate a subordinate in the group when compared with males which were peaceful as juveniles, whereas females which were more aggressive as juveniles tended to expel subordinates more often. Females produced significantly smaller clutches when paired to males which had helped more as a juvenile, despite the fact that adult males hardly provided direct brood care. There was no evidence that females with a high propensity to help when young, produced smaller clutches or eggs when adult, but they took longer to lay their first clutch when compared with females with a low propensity to help when young. These results suggest that variation in behavioural types might explain variation in cooperation, the extent of group‐living and reproductive decisions.     

Mixed primary culture and clonal analysis provide evidence that NG2 proteoglycan-expressing cells after spinal cord injury are glial progenitors

NG2(+) cells in the adult rat spinal cord proliferate after spinal cord injury (SCI) and are postulated to differentiate into mature glia to replace some of those lost to injury. To further study these putative endogenous precursors, tissue at 3 days after SCI or from uninjured adults was dissociated, myelin partially removed and replicate cultures grown in serum-containing or serum-free medium with or without growth factors for up to 7 days in vitro (DIV). Cell yield after SCI was 5-6 times higher than from the normal adult. Most cells were OX42(+) microglia/macrophages but there were also more than twice the normal number of NG2(+) cells. Most of these coexpressed A2B5 or nestin, as would be expected for glial progenitors. Few cells initially expressed mature astrocyte (GFAP) or oligodendrocyte (CC1) markers, but more did at 7 DIV, suggesting differentiation of glial precursors in vitro. To test the hypothesis that NG2(+) cells after SCI express progenitor-like properties, we prepared free-floating sphere and single cell cultures from purified suspension of NG2(+) cells from injured spinal cord. We found that sphere cultures could be passaged in free-floating subcultures, and upon attachment the spheres clonally derived from an acutely purified single cell differentiated into oligodendrocytes and rarely astrocytes. Taken together, these data support the hypothesis that SCI stimulates proliferation of NG2(+) cells that are glial progenitor cells. Better understanding the intrinsic properties of the NG2(+) cells stimulated by SCI may permit future therapeutic manipulations to improve recovery after SCI.     

Spoiled Brats: Is Extreme Juvenile Agonism in Ring‐Tailed Coatis (Nasua nasua) Dominance or Tolerated Aggression?

Ring‐tailed coatis exhibit an extreme form of juvenile agonism not found in other social mammals. Two groups of habituated, individually recognized, coatis were studied over a 2.5‐yr period in Iguazu National Park, Argentina. Dominance matrices were divided by year and group, resulting in four dominance hierarchies which were analyzed using the Matman computer program. Strong general patterns were seen in both groups during both years. Adult males (one per group) were the highest ranking individuals, followed by male juveniles, female juveniles, adult females, and male and female subadults. The pattern in which young, physically inferior individuals were able to outrank larger adults is different from other social mammal species in that the juvenile coatis aggressively defended food resources and directed aggression towards older individuals. These agonistic interactions may not reflect ‘dominance’ in the traditional sense, and appear to be a form of ‘tolerated aggression.’ This tolerated aggression leads to increased access to food, and should help juveniles during a period in which they need to rapidly gain weight and grow. Because this tolerance of juvenile aggression is reinforced through coalitionary support of juveniles by adult females, agonistic patterns are also consistent with the hypothesis that juvenile rank is being influenced by high degrees of relatedness within coati groups. Although some interesting parallels exist, there is little evidence indicating that these dominance patterns are the same as those found in other social mammals such as hyenas, lions, meerkats, or Cercopithicine primates.     

Connexins-Mediated Glia Networking Impacts Myelination and Remyelination in the Central Nervous System

In the central nervous system (CNS), the glial gap junctions are established among astrocytes (ASTs), oligodendrocytes (OLs), and/or between ASTs and OLs due to the expression of membrane proteins called connexins (Cxs). Together, the glial cells form a network of communicating cells that is important for the homeostasis of brain function for its involvement in the intercellular calcium wave propagation, exchange of metabolic substrates, cell proliferation, migration, and differentiation. Alternatively, Cxs are also involved in hemichannel function and thus participate in gliotransmission. In recent years, pathologic changes of oligodendroglia or demyelination found in transgenic mice with different subsets of Cxs or pharmacological insults suggest that glial Cxs may participate in the regulation of the myelination or remyelination processes. However, little is known about the underlying mechanisms. In this review, we will mainly focus on the functions of Cx-mediated gap junction channels, as well as hemichannels, in brain glial cells and discuss the way by which they impact myelination and remyelination. These aspects will be considered at the light of recent genetic and non-genetic studies related to demyelination and remyelination.     

Olig2/Plp-positive progenitor cells give rise to Bergmann glia in the cerebellum

NG2 (nerve/glial antigen2)-expressing cells represent the largest population of postnatal progenitors in the central nervous system and have been classified as oligodendroglial progenitor cells, but the fate and function of these cells remain incompletely characterized. Previous studies have focused on characterizing these progenitors in the postnatal and adult subventricular zone and on analyzing the cellular and physiological properties of these cells in white and gray matter regions in the forebrain. In the present study, we examine the types of neural progeny generated by NG2 progenitors in the cerebellum by employing genetic fate mapping techniques using inducible Cre–Lox systems in vivo with two different mouse lines, the Plp-Cre-ER^T2/Rosa26-EYFP and Olig2-Cre-ER^T2/Rosa26-EYFP double-transgenic mice. Our data indicate that Olig2/Plp-positive NG2 cells display multipotential properties, primarily give rise to oligodendroglia but, surprisingly, also generate Bergmann glia, which are specialized glial cells in the cerebellum. The NG2+ cells also give rise to astrocytes, but not neurons. In addition, we show that glutamate signaling is involved in distinct NG2+ cell-fate/differentiation pathways and plays a role in the normal development of Bergmann glia. We also show an increase of cerebellar oligodendroglial lineage cells in response to hypoxic–ischemic injury, but the ability of NG2+ cells to give rise to Bergmann glia and astrocytes remains unchanged. Overall, our study reveals a novel Bergmann glia fate of Olig2/Plp-positive NG2 progenitors, demonstrates the differentiation of these progenitors into various functional glial cell types, and provides significant insights into the fate and function of Olig2/Plp-positive progenitor cells in health and disease.     

Functional delay of myelination of auditory delay lines in the nucleus laminaris of the barn owl

In the barn owl, maps of interaural time difference (ITD) are created in the nucleus laminaris (NL) by interdigitating axons that act as delay lines. Adult delay line axons are myelinated, and this myelination is timely, coinciding with the attainment of adult head size, and stable ITD cues. The proximal portions of the axons become myelinated in late embryonic life, but the delay line portions of the axon in NL remain unmyelinated until the first postnatal week. Myelination of the delay lines peaks at the third week posthatch, and myelinating oligodendrocyte density approaches adult levels by one month, when the head reaches its adult width. Migration of oligodendrocyte progenitors into NL and the subsequent onset of myelination may be restricted by a glial barrier in late embryonic stages and the first posthatch week, since the loss of tenascin-C immunoreactivity in NL is correlated with oligodendrocyte progenitor migration into NL.