Genetics of Cerebellar and Neocortical Expansion in Anthropoid Primates: A Comparative Approach.

What adaptive changes in brain structure and function underpin the evolution of increased cognitive performance in humans and our close relatives? Identifying the genetic basis of brain evolution has become a major tool in answering this question. Numerous cases of positive selection, altered gene expression or gene duplication have been identified that may contribute to the evolution of the neocortex, which is widely assumed to play a predominant role in cognitive evolution. However, the components of the neocortex co-evolve with other functionally interdependent regions of the brain, most notably in the cerebellum. The cerebellum is linked to a range of cognitive tasks and expanded rapidly during hominoid evolution. Here we present data that suggest that, across anthropoid primates, protein-coding genes with known roles in cerebellum development were just as likely to be targeted by selection as genes linked to cortical development. Indeed, based on currently available gene ontology data, protein-coding genes with known roles in cerebellum development are more likely to have evolved adaptively during hominoid evolution. This is consistent with phenotypic data suggesting an accelerated rate of cerebellar expansion in apes that is beyond that predicted from scaling with the neocortex in other primates. Finally, we present evidence that the strength of selection on specific genes is associated with variation in the volume of either the neocortex or the cerebellum, but not both. This result provides preliminary evidence that co-variation between these brain components during anthropoid evolution may be at least partly regulated by selection on independent loci, a conclusion that is consistent with recent intraspecific genetic analyses and a mosaic model of brain evolution that predicts adaptive evolution of brain structure.

Development and the evolvability of human limbs.

The long legs and short arms of humans are distinctive for a primate, the result of selection acting in opposite directions on each limb at different points in our evolutionary history. This mosaic pattern challenges our understanding of the relationship of development and evolvability because limbs are serially homologous and genetic correlations should act as a significant constraint on their independent evolution. Here we test a developmental model of limb covariation in anthropoid primates and demonstrate that both humans and apes exhibit significantly reduced integration between limbs when compared to quadrupedal monkeys. This result indicates that fossil hominins likely escaped constraints on independent limb variation via reductions to genetic pleiotropy in an ape-like last common ancestor (LCA). This critical change in integration among hominoids, which is reflected in macroevolutionary differences in the disparity between limb lengths, facilitated selection for modern human limb proportions and demonstrates how development helps shape evolutionary change.

Characteristics of a group of Hubei Golden Snub-nosed Monkeys (Rhinopithecus roxellana hubeiensis) before and after major snow storms.

Natural disasters can negatively affect primate population demography and social group structure. A clear understanding of these effects has important implications for wildlife conservation. The worst snow storms in nearly five decades hit portions of southern and central China between January 10 and February 6, 2008, presenting a unique opportunity to observe their immediate effects on a previously studied group of Hubei Golden Snub-nosed Monkeys (Rhinopithecus roxellana hubeiensis) in temperate forests in Shennongjia Nature Reserve, Hubei Province, China. We recorded social and demographic characteristics of the group before and after the snow storms. The average group size decreased from 270 individuals before the storms to 197 individuals after the storms, a reduction of 27.2%. Adult females (30.1%), juveniles (38.1%) and infants (55.4%) suffered higher mortality than did adult males (15.7%). Despite age and sex-based differences in mortality, the ratios of adult males to adult females, adults to immatures and adult females to immatures remained similar before and after the storms. However, higher mortality among females, juveniles and infants may reduce the group's long-term potential for growth.

A comparison of the ontogeny of shape variation in the anthropoid scapula: functional and phylogenetic signal.

This article compares ontogenetic shape variation in the scapula of 17 anthropoid species using three-dimensional landmark-based geometric morphometrics. These data are used to investigate functional and phylogenetic signal in the major components of scapular variation and to evaluate the degree to which postnatal growth contributes to interspecific differences in shape. Results indicate that the shape of the infant and adult scapula is primarily associated with positional behavior (e.g., orthograde suspensory nonquadrupeds versus pronograde quadrupeds), but within this functional structure there is phylogenetic signal, particularly at infant stages. Growth most closely correlates with infant/adult shape and locomotor function. These results suggest that the shape of the infant scapula drives the pattern of postnatal scapular growth and adult morphology. As such, variation in postnatal growth is not the primary source of interspecific variation in adult shape. Instead, interspecific differences in scapular morphology are hypothesized to be the result of selection for variation in embryonic developmental processes that affect shape.

Frontal fusion: collapse of another anthropoid synapomorphy.

We test the hypothesis that the fused interfrontal suture of anthropoids is a uniquely distinguishing feature and a derived characteristic indicative of their monophyletic origin. Our survey of nonanthropoid primates and several archontan families indicates frontal fusion is widespread. It is most variable (fused, open or partially fused) inter- and intra-specifically among strepsirhines. The frontal bone is more commonly fused in living lemuroids and indrioids than among lorisoids. It appears to be fused regularly among Eocene adapids. Among nonanthropoid haplorhines, the interfrontal is fused in Tarsius, even in neonates and invariably in adults, probably also in all fossil tarsiiforms preserving the frontal bone, and in the late Eocene protoanthropoid Rooneyia. The plesiadapiform pattern remains uncertain, but fusion is ubiquitous among living tree shrews, colugos and bats. Distributional evidence implies that interfrontal fusion was present in the last common ancestor (LCA) of haplorhine primates and possibly in the LCA of euprimates as well. Anthropoids, therefore, cannot be defined cladistically by interfrontal fusion, not out of concern for homoplasy but because it is probably a primitive feature inherited from other taxa related to anthropoids. Fusion of the large anthropoid frontal bone, which was extended anteriorly to roof the orbits and expanded laterally in connection with a wide forebrain in the LCA of anthropoids and protoanthropoids, may have been preadaptive to the evolution of the postorbital septum. The zygomatico-frontal suture of the septum may provide an alternative mechanism for dissipating the calvarial strains of mastication formerly taken up by an open interfrontal suture.

Relationship of premaxillary bone and its sutures to deciduous dentition in nonhuman primates.

OBJECTIVE: The relationship of the human premaxillary bone (Pmx) to neighboring craniofacial structures is clouded by its embryonic union with the maxillary bone proper. Only humans among all primates have such early fusion of the premaxillomaxillary suture (PS). This study surveyed the relationship of the PS to the upper deciduous dentition in nonhuman primates, and describes the distribution of bone cells along the osseous margins of the Pmx. METHOD: Twenty-eight subadult primates were studied using gross, CT, and histologic observations. Location of the anterior deciduous dentition relative to the PS was assessed. In sections of selected specimens, observations of bone cells on the osseous boundaries of the Pmx were made. Osteopontin (OPN) immunohistochemistry was used to isolate osteoclastic binding sites along the Pmx boundaries. RESULTS: The PS was consistently found between deciduous incisor and canine in strepsirrhines of all ages, whereas the suture passed variably closer to the incisor or canine in haplorhines. In all species, the anterior part of the Pmx was nonarticulating and mostly osteoblastic, except for osteoclastic margins adjacent to dentition and the nasal fossa. Superolaterally, the osteogenic fronts of the PS were osteoblastic, while more inferiorly, at the level of the deciduous canine, the PS was often osteoclastic. Results from OPN immunohistochemistry support the findings on bone cell distribution. CONCLUSION: Bone cell distribution patterns in perinatal nonhuman primates resemble those described for the prenatal human Pmx, suggesting that differences among species relate to magnitude rather than the pattern of osteogenesis.

Patterns of correlation and covariation of anthropoid distal forelimb segments correspond to Hoxd expression territories.

Anthropoids in general and hominoids in particular exhibit differential adaptations in forearm and digital skeletal proportions to a diverse array of locomotor modes. Hox genes act as selector genes with spatially regulated expression patterns during development. Their expression in the forelimb appears to define modules that specify differential skeletal growth. Here we explore forelimb skeletal proportions in a large sample of anthropoids from a background provided by Hoxd expression patterns in late-stage murine embryonic forelimbs. Interspecific correlation and principal components analyses of primate forelimb data indicate that morphological variation in anthropoids reflects well-defined developmental modules downstream of Hoxd expression. The phalanges of digit one appear to represent a single growth module, whereas the metacarpals and manual phalanges of the posterior digits correspond to a second, independent, expression territory that extends proximally into the distal zeugopod. In particular, hominoids show very high correlations among the posterior digits and the independence of digit one. In addition, the distal radius is generally highly correlated with the posterior digits and not digit one. Relying on established functional differences among Hox paralogs, we present a model that parsimoniously explains hominoid forearm and digital proportions as a consequence of downstream effects of Hox. We, therefore, suggest that Hox-defined developmental modules have served as evolutionary modules during manual evolution in anthropoids.

Ontogeny of the nasolacrimal duct in primates: functional and phylogenetic implications.

The ontogeny of the nasolacrimal ducts (NLD) and canals (NLC) are investigated in strepsirrhine and haplorhine primates. Developmental series of serially sectioned fetal, perinatal and adult specimens, in combination with juvenile and adult skulls subjected to high-resolution computed tomography, reveal that the vertical NLC and NLD of adult tarsiers and anthropoids are produced by the degeneration of a more horizontal anterior arm of the NLD that is present only transiently in haplorhines, but is maintained throughout life in strepsirrhines. This degeneration manifests as an 'unzipping' of the anterior arm by means of progressive enlargement (in a rostral direction) of a caudally placed opening of the NLD (at the base of the vertical NLC), followed by breakdown of the resulting epithelial groove. The similar mode by which the anterior arm of the membranous NLD degenerates in tarsiers and anthropoids strongly suggests that the conditions in these two taxa are homologous, and provides additional evidence for a monophyletic Haplorhini. The functional relationship between the nasolacrimal duct and the vomeronasal organ is reviewed in light of this evidence, and it is suggested that these changes in the haplorhine NLD were functionally linked to the development of anatomical haplorhinism of the oronasal complex.

Ontogenetic bases of canine dimorphism in anthropoid primates.

This study tests hypotheses regarding the ontogeny of canine tooth size dimorphism in five anthropoid primate species (Saguinus fuscicollis, Macaca mulatta, Cercocebus atys, Papio hamadryas, and Mandrillus sphinx). Canine measurements and chronological age data are analyzed to determine if bimaturism, a sex difference in the age at which eruption ceases, accounts for canine tooth sexual dimorphism. Canine height measurements are evaluated through a variety of regression techniques. Results show a lack of sexual dimorphism in Saguinus. While size dimorphism is absent in the deciduous teeth of all species analyzed, the adult teeth in cercopithecines become increasingly dimorphic through ontogeny. Female adult tooth eruption regularly precedes male tooth eruption, and regression-based eruption trajectories for both sexes intersect at about the age at which the female tooth reaches adult size. Males erupt the tooth later and more rapidly than females. Males also reach a larger adult size than females by erupting the tooth for much longer periods of time. Bimaturism is primary in the production of dimorphism, but rates of eruption show modest variation. These results point to the scheduling of sexual selection through intermale competition as a primary factor determining male eruption timing, rates of eruption, and adult size. Life history factors may play a role in determining the relations between the scheduling of intrasexual competition and canine eruption. Female contributions to sexual dimorphism are apparent in these species, suggesting that similar levels of dimorphism can be attained through diverse ontogenetic pathways.

Expression of BDNF and TrkB receptor subtypes in the postnatal developing Purkinje cells of monkey cerebellum.

In the previous study, we have shown the complementary expression of TrkB subtypes (TK+ and T1) in the adult monkey cerebellar cortex. In this study, to clarify when that expression pattern appeared, we examined the expressions of TrkB subtypes and its ligand brain-derived neurotrophic factor (BDNF) by immunohistochemistry and Western blot analysis. At the newborn stage, both TK+ and T1 were expressed uniformly in the cerebellar cortex. At postnatal month 3.5, the uneven expression of TrkB subtypes was observed, while the BDNF immunoreactivity was strongly detected in all regions of the cerebellar cortex. The expression patterns of TrkB subtypes and BDNF at both postnatal month 6 and year 7 were the same as those at postnatal month 3.5. Western blot analysis demonstrated that TK+ and T1 were expressed at high levels in the synaptic membrane from newborn to adult stages. Furthermore, the dimerization of TrkB subtypes changed at postnatal month 3, which was similar to the adult pattern: at the newborn stage, the TK+ and TK- homodimers; after postnatal month 3.5, the TK+ and TK- homodimers, and the TK+/TK- heterodimer. These findings suggest that the localization of TrkB subtypes in each Purkinje would be changed at postnatal month 3.5, resulting in the uneven expression of TrkB subtypes and the change of TrkB dimerization.

Cellular mechanisms in retinal vascular development.

Since the pioneering work of Ashton and others, the primate retina has been thought to vascularize by a vasculogenic linkage of endothelial precursor cells. Recent investigations using specific histologic and morphologic criteria question the contribution of vasculogenesis to retinal development. Instead, in primates and mice cells previously designated as retinal angioblasts have been identified as astrocytes that form a vascular-like plexus preceding vessel invasion. Further, in primates and mice retinal vascularization proceeds via angiogenic sprouting from pre-existing vessels in all regions and stages. However, the developing retinal vasculature may utilize novel sources of endothelial cells, such as recruitment of circulating stem cells and redeployment of mural cells from regressing vessel segments. These results provide a framework for study of retinal vascular development, validate the common use of perinatal retinal models in angiogenesis research, and clarify the cellular basis of retinopathy of prematurity.

Age-related changes in GluR2 and NMDAR1 glutamate receptor subunit protein immunoreactivity in corticocortically projecting neurons in macaque and patas monkeys.

A distinct subpopulation of neurons forming long corticocortical projections in the association neocortex is highly vulnerable to the degenerative process in Alzheimer's disease. However, the degree to which age-related molecular and morphologic alterations of identifiable neuronal populations reflects early cellular degeneration leading to functional deficits has not yet been fully investigated in the aging brain. We performed an immunohistochemical analysis of neurons forming short and long corticocortical projections in young and old monkeys using antibodies to the GluR2 and NMDAR1 glutamate receptor subunit proteins. Projection neurons differed in their expression of these receptor subunits, as GluR2 was less prevalent than NMDAR1 among retrogradely labeled neurons. Long and short corticocortical pathways in old animals demonstrated a considerable decrease in the proportions of projection neurons containing GluR2 and NMDAR1, an observation that was particularly consistent in the case of GluR2. No age-related differences were observed in distribution of neurofilament protein in either type of projection neurons. These data suggest that cortical neurons furnishing long and short corticocortical projections display consistent neurochemical changes during aging and that a differential decrease in cellular expression of glutamate receptor subunit proteins occurs. The fact that in aging these neurons have lower levels of GluR2 than in young individuals, but comparatively higher levels of NMDAR1 than GluR2, may render them prone to calcium-mediated excitotoxicity, which in humans may be related to the selective vulnerability of such neurons during the course of Alzheimer's disease. Also, it is apparent that age-related neuronal changes are quite subtle and involve subcellular components of the cortical circuits rather than major morphologic alterations.

Rod photoreceptor maturation does not vary with retinal eccentricity in mammalian retina.

PURPOSE: Test the hypothesis that the development of mammalian rod outer segments (ROS) varies with retinal eccentricity. METHODS: During the period of photoreceptor cell development, ROS lengths, opsin mRNA and (rhod)opsin were measured in central and peripheral retina of cows and pigmented rats. Published ROS length and/or rhodopsin data from albino rats, cows and monkeys were re-analyzed. Logistic growth curves were fitted to the newly obtained and published data. Within a species, growth in central and peripheral regions was compared. RESULTS: The logistic growth curves fit all the data well and provide an excellent view of the developmental increases in ROS length, opsin mRNA and (rhod)opsin in each retinal region. Within a species, the growth curves for ROS length, opsin mRNA and (rhod)opsin concentration are superimposable. The age at which ROS length reaches 50% of its adult value is invariant with eccentricity. An exception to this pattern is the simian parafoveal ROS, which appears to have a delayed course of development. CONCLUSIONS: The hypothesis is disproved. Unlike rod photoreceptor cell genesis, ROS development is invariant with retinal eccentricity. Primate parafoveal ROS appear to have a different pattern of development.

Active emmetropization--evidence for its existence and ramifications for clinical practice.

There is increasing evidence from animal studies in support of the concept of an active emmetropization mechanism which has potentially important clinical ramifications for the management of refractive errors. Recent research into refractive development and emmetropization is reviewed, with emphasis given to work involving the chick, tree shrew and monkey, which represent the three most widely used animal models in this field. The findings of this research are reviewed in a clinical context. Compensatory eye growth responses to focusing errors imposed by lenses represent the most compelling evidence for active emmetropization. These observations are complemented by other evidence showing recovery from induced refractive errors such as form-deprivation myopia. Of the animals listed above, chicks show the most impressive emmetropization, being able to compensate fully (using choroidal and scleral mechanisms) to lens powers ranging from +15 D to -10 D. The range of lens powers eliciting appropriate compensatory responses is narrower in the tree shrew and monkey, and the response patterns generally are also more complex to interpret. These data relate to young animals and together indicate refractive plasticity during development. Extrapolation of these findings to humans predicts that natural emmetropization will be inhibited in neonates by early intervention with prescription lenses, and that refractive correction of myopia will lead to accelerated progression. This convincing evidence for active emmetropization warrants due consideration in developing clinical management strategies for refractive errors.

Activity and attention in zinc-deprived adolescent monkeys.

Lethargy is characteristic of malnourished populations, but little is known about the biologic mechanism or consequences for cognitive performance. In the current experiment, 24-h activity patterns and performance of an attention task were studied in adolescent female monkeys (18-33 mo of age, n = 10/group) under conditions of moderate dietary zinc deprivation (2 micrograms Zn/g diet) and adequate dietary zinc (50 micrograms Zn/g). There were progressive decreases in daytime activity levels in the zinc-deprived group followed by slowing of growth around the time of the growth spurt. Attention performance was also impaired before the onset of growth retardation. Zinc-deprived monkeys failed to show the shift to later initiation of the rest phase of the diurnal cycle seen in controls in late adolescence. These data support previous findings that activity and attention can be affected during early stages of zinc deprivation before the onset of growth retardation.

Socioecology and the ontogeny of sexual size dimorphism in anthropoid primates.

This study examines statistical correlations between socioecological variables (including measures of group composition, intermale competition, and habitat preference) and the ontogeny of body size sexual dimorphism in anthropoid primates. A regression-based multivariate measure of dimorphism in body weight ontogeny is derived from a sample of 37 species. Quantitative estimates of covariation between socioecological variables and this multivariate measure are evaluated. Statistically significant covariation between the ontogeny of dimorphism and socioecological variables, with the possible exception of habitat preference, is observed. Sex differences in ontogeny are lacking in species that exhibit low levels of intermale competition and are classifiable as species with monogamous/polyandrous mating systems. Among dimorphic species, two modes of dimorphic growth are apparent, which seem to be related to different kinds of group compositions. Multimale/multifemale species tend to become dimorphic through bimaturism (sex differences in duration of growth) with minimal sex differences in growth rate. Single-male/multifemale species tend to attain dimorphism through differences in rate of growth, often with limited bimaturism. Measures of intermale competition may also covary with these modes of dimorphic growth, but the relations among these variables are sometimes ambiguous. Correlations between dimorphic growth and behavioral variables may reflect alternative life history strategies in primates. Specifically, the ways in which risks faced by subadult males are distributed and the relations of these risks to growth rates seem to influence the evolution of size ontogenies. The absence of dimorphic ontogeny in some species can be tied to similar distributions of risk in each sex. In taxa that become dimorphic primarily through rate differences in growth, the lifetime distribution of risks for males may change rapidly. In contrast, males may face a pattern of uniformly changing or stable risk in species that become dimorphic through bimaturism. Finally, much variation recorded by this study remains unexplained, providing additional evidence of the need to specially examine female ontogeny before primate body size dimorphism can be satisfactorily explained.

Localization and developmental expression of the NMDA receptor subunit NR2A in the mammalian retina.

The localization of the N-methyl-D-aspartate receptor subunit NR2A was studied, by using light microscopic immunocytochemistry, in the retina of adult rat, rabbit, cat, and monkey. Strong, punctate immunolabeling was observed in the inner plexiform layer indicating a synaptic localization of the NR2A subunit. The punctate labeling was concentrated in two bands corresponding to the on- and off-sublaminae of the inner plexiform layer. The punctate character of immunofluorescence suggested a synaptic localization of the receptor. This was confirmed by electron microscopy of immunostained adult rat retina. The staining was localized postsynaptic to cone bipolar cells, and only one of the two postsynaptic elements of the dyad was labeled. Staining was not observed at extrasynaptic plasma membranes. In situ hybridization of adult rat retina showed expression of the NR2A subunit in virtually all ganglion cells and displaced amacrine cells in the ganglion cell layer and in a subset of amacrine cells in the inner nuclear layer. The postnatal developmental expression of the NR2A subunit was studied in rat retina by light microscopic immunocytochemistry. Punctate immunolabeling appeared prior to eye opening, and the developmental profile of NR2A could be compatible with a role in development of circuitry in the inner plexiform layer.

Development of inferior temporal cortex in the monkey.

Inferior temporal (IT) cortex is critical for visual pattern recognition in adult primates. However, the functional development of IT cortex appears to be incomplete until late in the first year of life in monkeys and probably beyond. Responses of neurons in IT are substantially weaker, of longer latency, and more susceptible to anesthesia within at least the first half year of life. In addition, refinement of connections of IT, particularly those with regions in the opposite hemisphere and with regions related to memory and attention, continues for at least several months after birth. Moreover, many of the pattern recognition functions that IT supports in adulthood themselves show a very protracted period of development, and damage to IT cortex in infancy appears to have relatively little effect on pattern recognition abilities, despite the pronounced effects of comparable damage in adulthood. These findings all suggest that IT undergoes an extended period of postnatal development, during which both visual experience and the maturation of other brain structures may contribute to the emergence of mechanisms of pattern recognition within IT. In other respects, fundamental characteristics of IT emerge quite early. For example, despite their weaker responses, IT neurons have adult-like patterns of responsiveness--including pronounced form selectivity and large bilateral receptive fields--as early as we were able to test (approximately 6 weeks). Thus, IT cortex appears to be prewired with (or predisposed to develop rapidly) neural circuitry sufficient to produce basic properties remarkably similar to those found in the adult animal. Future studies of IT cortex will need to address the development of signals related to perceptual constancies and to formation and retrieval of visual object memories, the development of interactions with other regions involved in visual recognition (particularly frontal cortex), and the specific mechanisms underlying various types of plasticity present in IT cortex in both developing and mature primates.

Ontogenetic correlates of diet in anthropoid primates.

This study assesses ontogenetic correlates of diet in anthropoid primates. Associations between body weight growth, adult size, and diet are evaluated for a sample of 42 primate species, of which 8 are classifiable as "folivores." The hypothesis that folivores show a pattern of growth that differs from "nonfolivores" is tested. Ontogenetic variation is summarized through use of parametric and nonparametric regression analysis. Several analytical techniques, including broad interspecific and detailed comparisons among species of similar adult size, are applied. This investigation indicates a clear association between body weight ontogeny and diet: folivorous species grow more rapidly over a shorter duration than comprably sized nonfolivorus species. A positive correlation between adult size and diet is not unambiguously established in this sample. A threshold (at around 1 kg) below which insectivory is very common may adequately characterize the association between adult size and diet in anthropoid primates. Above this threshold, adult size does not appear to covary predictably with diet. Evolutionary correlates of the ontogenetic pattern seen in folivores may include a variety of factors. The distinctive pattern of development in folivores may relate to the profile of ecological and social risks that these species face. Morphophysiological advantages to rapid growth may relate to a need for accelerated alimentary (dental and gut) development. The implications of ontogenetic variation in folivores are discussed.

Edridge-Green Lecture. Competition and cooperation in visual development.

Studies of the effect of visual deprivation on cells in the lateral geniculate nucleus (LGN) show that there are two distinct sensitive periods in the monkey during which different reactions between the visual pathways related to the two eyes predominate and requirements for recovery from deprivation differ. The first extends from birth to about 8 weeks of age. The main interaction between the pathways from the two eyes is competitive, segregation of cortical ocular dominance columns occurs during this early period and monocular deprivation results initially in hypertrophy of undeprived LGN cells, with later parallel shrinkage of both deprived and undeprived parvocellular cells. Simply reopening the closed eye produces no recovery but reverse suture is effective in reversing some of the changes. The second sensitive period starts from about 8 weeks of age, although the peak of the later sensitivity appears to be at 7-9 months of age and some effect is still present at 12-18 months. During this later phase a cooperative interaction between the pathways related to the two eyes is necessary for normal development and in the absence of this selective shrinkage of both deprived and undeprived parvocellular LGN cells occurs. Simply reopening an eye during this late sensitive period allows recovery of these cells to normal size.