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Mind the (sr)GAP - roles of Slit-Robo GAPs in neurons, brains and beyond.
The Slit-Robo GTPase-activating proteins (srGAPs) were first identified as potential Slit-Robo effectors that influence growth cone guidance. Given their N-terminal F-BAR, central GAP and C-terminal SH3 domains, srGAPs have the potential to affect membrane dynamics, Rho family GTPase activity and other binding partners. Recent research has clarified how srGAP family members act in distinct ways at the cell membrane, and has expanded our understanding of the roles of srGAPs in neuronal and non-neuronal cells. Gene duplication of the human-specific paralog of srGAP2 has resulted in srGAP2 family proteins that may have increased the density of dendritic spines and promoted neoteny of the human brain during crucial periods of human evolution, underscoring the importance of srGAPs in the unique sculpting of the human brain. Importantly, srGAPs also play roles outside of the nervous system, including during contact inhibition of cell movement and in establishing and maintaining cell adhesions in epithelia. Changes in srGAP expression may contribute to neurodevelopmental disorders, cancer metastasis and inflammation. As discussed in this Review, much remains to be discovered about how this interesting family of proteins functions in a diverse set of processes in metazoans and the functional roles srGAPs play in human disease.
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Cellular and Molecular Mechanisms Linking Human Cortical Development and Evolution.
The cerebral cortex is at the core of brain functions that are thought to be particularly developed in the human species. Human cortex specificities stem from divergent features of corticogenesis, leading to increased cortical size and complexity. Underlying cellular mechanisms include prolonged patterns of neuronal generation and maturation, as well as the amplification of specific types of stem/progenitor cells. While the gene regulatory networks of corticogenesis appear to be largely conserved among all mammals including humans, they have evolved in primates, particularly in the human species, through the emergence of rapidly divergent transcriptional regulatory elements, as well as recently duplicated novel genes. These human-specific molecular features together control key cellular milestones of human corticogenesis and are often affected in neurodevelopmental disorders, thus linking human neural development, evolution, and diseases.
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Hominoid SVA-lncRNA AK057321 targets human-specific SVA retrotransposons in SCN8A and CDK5RAP2 to initiate neuronal maturation.
SINE-VNTR-Alu (SVA) retrotransposons arose and expanded in the genome of hominoid primates concurrent with the slowing of brain maturation. We report genes with intronic SVA transposons are enriched for neurodevelopmental disease and transcribed into long non-coding SVA-lncRNAs. Human-specific SVAs in microcephaly CDK5RAP2 and epilepsy SCN8A gene introns repress their expression via transcription factor ZNF91 to delay neuronal maturation. Deleting the SVA in CDK5RAP2 initiates multi-dimensional and in SCN8A selective sodium current neuronal maturation by upregulating these genes. SVA-lncRNA AK057321 forms RNA:DNA heteroduplexes with the genomic SVAs and upregulates these genes to initiate neuronal maturation. SVA-lncRNA AK057321 also promotes species-specific cortex and cerebellum-enriched expression upregulating human genes with intronic SVAs (e.g., HTT, CHAF1B and KCNJ6) but not mouse orthologs. The diversity of neuronal genes with intronic SVAs suggest this hominoid-specific SVA transposon-based gene regulatory mechanism may act at multiple steps to specialize and achieve neoteny of the human brain.
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The ontogeny of human gyrification.
During development the human cortex changes from a smooth lissencephalic structure to one that is highly convoluted. Increases in the degree of cortical folding are associated with brain size only for the first part of brain growth; during the second half, differences in cortical folding match those of brain size, resulting in no change in the degree of folding. When the degree of cortical folding is studied as a function of age, a brief postnatal overshoot, an effect of brain size, is observed. The analysis suggests that the mechanical hypothesis of cortical buckling can best explain the degree of cortical folding, but that other hypotheses, like gyrogenesis, are required to explain the placement and orientation of sulci. The adult asymptote in degree of cortical folding is associated with the onset and disappearance of single subplate lamina, suggesting that subplate:cortical plate associations should be examined as causal for gyrification. Areas whose sulci differ in length between the two hemispheres have similar degrees of convolutedness, supporting interpretations that the sizes of gyri are asymmetric in the two hemispheres. The ontogenetic data support the thesis that human cortical proportions evolved when the brain enlarged in size and that the process was not one of neoteny.
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Cortical evolution and human behaviour.
All mammals have complex behaviours but these are generally stereotyped in nature and lack the flexibility of human behaviour. Can the flexibility of human behaviour be understood as an evolutionary extension of previous behaviours or is it a departure? Theories pertaining to this question have a long history including, now refuted, theories on neoteny. This paper, using an evolutionary developmental biology approach, outlines some existing theories and suggests some novel ideas. Previous trends during brain evolution are determined by outlining the phylogeny and ontogeny of the six layered mammalian isocortex with particular reference to the primate lineage. These evolutionary trends are extrapolated to hominids to postulate the effect of increasingly large brains. The palaeoanthropological literature is cited to debate the nature and time course of behavioural change during hominid evolution. In particular, when was truly flexible behaviour first evident, and did it occur gradually or suddenly? The proposed isocortical and behavioural changes during hominid evolution are then equated to determine if modern human behaviour can be seen as part of a continuum. It is concluded that a continuation of previous trends in isocortical evolution maybe inadequate to explain human behavioural flexibility. Several possible departures from previous trends that would be compatible with increased behavioural flexibility are suggested. These mainly relate to evolutionary changes in the later stages of isocortical development and in particular during the activity-dependant phase when cortico-cortical connections are refined.
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Xenotransplanted Human Cortical Neurons Reveal Species-Specific Development and Functional Integration into Mouse Visual Circuits.
How neural circuits develop in the human brain has remained almost impossible to study at the neuronal level. Here, we investigate human cortical neuron development, plasticity, and function using a mouse/human chimera model in which xenotransplanted human cortical pyramidal neurons integrate as single cells into the mouse cortex. Combined neuronal tracing, electrophysiology, and in vivo structural and functional imaging of the transplanted cells reveal a coordinated developmental roadmap recapitulating key milestones of human cortical neuron development. The human neurons display a prolonged developmental timeline, indicating the neuron-intrinsic retention of juvenile properties as an important component of human brain neoteny. Following maturation, human neurons in the visual cortex display tuned, decorrelated responses to visual stimuli, like mouse neurons, demonstrating their capacity for physiological synaptic integration in host cortical circuits. These findings provide new insights into human neuronal development and open novel avenues for the study of human neuronal function and disease. VIDEO ABSTRACT.
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The role of immaturity in human development.
The possibility that infants' and young children's immature behaviors and cognitions are sometimes adaptive is explored and interpreted in terms of evolutionary theory. It is argued that developmental immaturity had an adaptive role in evolution and continues to have an adaptive role in human development. The role of developmental retardation in human evolution is discussed, followed by an examination of the relation between humans' extended childhood and brain plasticity. Behavioral neoteny, as exemplified by play, is examined, as are some potentially adaptive aspects of infants' perception and cognition that limit the amount of information they can process. Aspects of immature cognition during early childhood that may have some contemporaneous adaptive value are also discussed. It is proposed that viewing immaturity as sometimes adaptive to the developing child alters how children and their development are viewed.
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A comprehensive transcriptional map of primate brain development.
The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high-resolution transcriptional atlas of rhesus monkey (Macaca mulatta) brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical division of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons. Cortical layers and areas acquire adult-like molecular profiles surprisingly late in postnatal development. Disparate cell populations exhibit distinct developmental timing of gene expression, but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, although approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny compared to monkey.
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Depression in adolescence and young adulthood: the difficulty to integrate motivational/emotional systems.
Depression is presented as a multi-factorial bio-psycho-social expression that has evolved primarily as an effect of stressors related to the motivational/emotional systems that regulate the BrainMind in our relationship with conspecifics. These stressors may be caused by two sources of threat, firstly, the loss of bonding with the caregiver and later with a partner and/or group which relates to the SEPARATION (PANIC/GRIEF) system, secondly, social defeat as an expression of the social competition and social dominance. The sexual maturity drives the individual to social competition and social dominance, even if the latter often occurs before sexual maturity, e.g., chickens, dogs, non-human primates, and humans. Depression is an evolutionarily conserved mechanism in mammals to terminate both separation anxiety, so as to protect the vulnerable social brain from the consequences of prolonged separation anxiety, and the stress of social competition when social defeat is predictable. Adolescence and Young adulthood are particularly susceptible to these two types of threat because of human developmental characteristics that are summarized by the term neoteny. This refers to the slowing down of growth and development, resulting in both a prolonged period of dependence on a caring/protective adult and the persistence of juvenile characteristics throughout life. Therefore, neoteny makes the transition from childhood to sexual maturity more dramatic, making the integration of the SEPARATION (PANIC/GRIEF) system with the dynamics of social competition and dominance more stressful and a source of depression. Stress is an expression of the HPA-Hypothalamic-Pituitary-Adrenal axis that articulates with other systems, mainly the autonomic nervous system and the immune-inflammatory system. The latter is believed to be one of the most significant components in the dynamics of depressive processes, connected to the prodromes of its activation in childhood, under the pressure of environmental and relational stressors which can lead to learned helplessness. The recurrence of stressors makes it easier for the immune-inflammatory system to be activated in later life, which could make a significant contribution to the establishment of a depressive disease. The possible contribution of children's identification processes with their parents' depressive personalities through observational learning is considered.
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The cost of language: functionally over-dominant language circuits in the human brain may limit cognitive abilities and non-verbal executive functions.
Evolutionarily, the most recent connective system in the human brain is the language circuitry. However, its presence may impose restrictions on higher executive functions apparent as non-verbal talents in art, science, and management- essentially a conflict between talking and doing. Since the associative cortex underlies thinking, the question then is how much of it is assigned to language functions, and how much is left for associative networks that support non-verbal functions such as planning and parallel processing. Arguments: (i) The determinant of neocortical network organization is the motor cortex, which acts as the main attractor for all processes in the hemispheres yet is split in two sub-attractors formed by disproportionally enlarged zones of origins for two bundles, the corticospinal tract co-driving movements of arms and hands, and the corticobulbar tract to the motor nuclei of the cranial nerves innervating the vocal tract, tongue and face. (ii) This arrangement must entail different functional properties of the associated networks. The language network faces executive limits because the linear generation of words becomes dominated by cerebellar feedback from lingual processing ("one word generates the next"), while the non-verbal networks have more freedom in generating mental goals and movements. (iii) Functional imbalance between these neocortical networks results from altered connections caused by neuronal competition during brain development, either by epigenetic events or by selectable genetic factors. (iv) The descent of the larynx in humans during the paleolithic period and the following self-domestication and neoteny during the last 30,000 years have favored the expansion of the cerebral language network. Voices gained prosody and melody, thereby transmitting fine-grained levels of emotions between individuals, facilitating the evolution of collective cooperation in agricultural economies. On the other hand, with the advent of densely populated kingdom states, emotional voicing also enabled mass control of people for warfare and social stratification of societies. This new environment entailed genetic adaptation of a large population segment resulting in moderately lowered cognition, firstly by expansion of the language network permitting emotional association of simple memes and words, possibly supported by additional mechanisms conserving a child-like stage of brain development responsible for word-linked beliefs.