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Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition.
Human-specific (HS) genes have been implicated in brain evolution, but their impact on human neuron development and diseases remains unclear. Here, we study SRGAP2B/C, two HS gene duplications of the ancestral synaptic gene SRGAP2A, in human cortical pyramidal neurons (CPNs) xenotransplanted in the mouse cortex. Downregulation of SRGAP2B/C in human CPNs led to strongly accelerated synaptic development, indicating their requirement for the neoteny that distinguishes human synaptogenesis. SRGAP2B/C genes promoted neoteny by reducing the synaptic levels of SRGAP2A,thereby increasing the postsynaptic accumulation of the SYNGAP1 protein, encoded by a major intellectual disability/autism spectrum disorder (ID/ASD) gene. Combinatorial loss-of-function experiments in vivo revealed that the tempo of synaptogenesis is set by the reciprocal antagonism between SRGAP2A and SYNGAP1, which in human CPNs is tipped toward neoteny by SRGAP2B/C. Thus, HS genes can modify the phenotypic expression of genetic mutations leading to ID/ASD through the regulation of human synaptic neoteny.
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SYNGAP1 deficiency disrupts synaptic neoteny in xenotransplanted human cortical neurons in vivo.
Human brain ontogeny is characterized by a considerably prolonged neotenic development of cortical neurons and circuits. Neoteny is thought to be essential for the acquisition of advanced cognitive functions, which are typically altered in intellectual disability (ID) and autism spectrum disorders (ASDs). Human neuronal neoteny could be disrupted in some forms of ID and/or ASDs, but this has never been tested. Here, we use xenotransplantation of human cortical neurons into the mouse brain to model SYNGAP1 haploinsufficiency, one of the most prevalent genetic causes of ID/ASDs. We find that SYNGAP1-deficient human neurons display strong acceleration of morphological and functional synaptic formation and maturation alongside disrupted synaptic plasticity. At the circuit level, SYNGAP1-haploinsufficient neurons display precocious acquisition of responsiveness to visual stimulation months ahead of time. Our findings indicate that SYNGAP1 is required cell autonomously for human neuronal neoteny, providing novel links between human-specific developmental mechanisms and ID/ASDs.
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CTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny.
Human-specific genes are potential drivers of brain evolution. Among them, SRGAP2C has contributed to the emergence of features characterizing human cortical synapses, including their extended period of maturation. SRGAP2C inhibits its ancestral copy, the postsynaptic protein SRGAP2A, but the synaptic molecular pathways differentially regulated in humans by SRGAP2 proteins remain largely unknown. Here, we identify CTNND2, a protein implicated in severe intellectual disability (ID) in Cri-du-Chat syndrome, as a major partner of SRGAP2. We demonstrate that CTNND2 slows synaptic maturation and promotes neuronal integrity. During postnatal development, CTNND2 moderates neuronal excitation and excitability. In adults, it supports synapse maintenance. While CTNND2 deficiency is deleterious and results in synaptic loss of SYNGAP1, another major ID-associated protein, the human-specific protein SRGAP2C, enhances CTNND2 synaptic accumulation in human neurons. Our findings suggest that CTNND2 regulation by SRGAP2C contributes to synaptic neoteny in humans and link human-specific and ID genes at the synapse.
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A cross-species proteomic map reveals neoteny of human synapse development.
The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood1,2. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of RhoGEF signalling in human neurons delays morphological maturation of dendritic spines and functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell-type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation.
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Transcriptional neoteny in the human brain.
In development, timing is of the utmost importance, and the timing of developmental processes often changes as organisms evolve. In human evolution, developmental retardation, or neoteny, has been proposed as a possible mechanism that contributed to the rise of many human-specific features, including an increase in brain size and the emergence of human-specific cognitive traits. We analyzed mRNA expression in the prefrontal cortex of humans, chimpanzees, and rhesus macaques to determine whether human-specific neotenic changes are present at the gene expression level. We show that the brain transcriptome is dramatically remodeled during postnatal development and that developmental changes in the human brain are indeed delayed relative to other primates. This delay is not uniform across the human transcriptome but affects a specific subset of genes that play a potential role in neural development.
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Mitochondria metabolism sets the species-specific tempo of neuronal development.
Neuronal development in the human cerebral cortex is considerably prolonged compared with that of other mammals. We explored whether mitochondria influence the species-specific timing of cortical neuron maturation. By comparing human and mouse cortical neuronal maturation at high temporal and cell resolution, we found a slower mitochondria development in human cortical neurons compared with that in the mouse, together with lower mitochondria metabolic activity, particularly that of oxidative phosphorylation. Stimulation of mitochondria metabolism in human neurons resulted in accelerated development in vitro and in vivo, leading to maturation of cells weeks ahead of time, whereas its inhibition in mouse neurons led to decreased rates of maturation. Mitochondria are thus important regulators of the pace of neuronal development underlying human-specific brain neoteny.
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Olduvai domain expression downregulates mitochondrial pathways: implications for human brain evolution and neoteny.
Encoded by the NBPF gene family, Olduvai (formerly DUF1220) protein domains have undergone the largest human lineage-specific copy number expansion of any coding region in the genome. Olduvai copy number shows a linear relationship with several brain size-related measures and cortical neuron number among primates and with normal and disease-associated (micro- and macrocephaly) variation in brain size in human populations. While Olduvai domains have been shown to promote proliferation of neural stem cells, the mechanism underlying such effects has remained unclear. Here, we investigate the function of Olduvai by transcriptome and proteome analyses of cells overexpressing NBPF1, a gene encoding 7 Olduvai domains. Our results from both RNAseq and mass spectrometry approaches suggest a potential downregulation of mitochondria. In our proteomics study, a Gene Ontology (GO) enrichment analysis for the downregulated proteins revealed a striking overrepresentation of the biological process related to the mitochondrial electron transport chain (p value: 1.81e-11) and identified deregulation of the NADH dehydrogenase activity (p value: 2.43e-11) as the primary molecular function. We verify the reduction of apparent mitochondria via live-cell imaging experiments. Given these and previous Olduvai findings, we suggest that the Olduvai-mediated, dosage-dependent reduction in available energy via mitochondrial downregulation may have resulted in a developmental slowdown such that the neurogenic window among primates, and most extremely in humans, was expanded over a greater time interval, allowing for production of greater numbers of neurons and a larger brain. We further suggest that such a slowdown may extend to other developmental processes that also exhibit neotenic features.
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Transgenic rhesus monkeys carrying the human MCPH1 gene copies show human-like neoteny of brain development.
Brain size and cognitive skills are the most dramatically changed traits in humans during evolution and yet the genetic mechanisms underlying these human-specific changes remain elusive. Here, we successfully generated 11 transgenic rhesus monkeys (8 first-generation and 3 second-generation) carrying human copies of MCPH1, an important gene for brain development and brain evolution. Brain-image and tissue-section analyses indicated an altered pattern of neural-cell differentiation, resulting in a delayed neuronal maturation and neural-fiber myelination of the transgenic monkeys, similar to the known evolutionary change of developmental delay (neoteny) in humans. Further brain-transcriptome and tissue-section analyses of major developmental stages showed a marked human-like expression delay of neuron differentiation and synaptic-signaling genes, providing a molecular explanation for the observed brain-developmental delay of the transgenic monkeys. More importantly, the transgenic monkeys exhibited better short-term memory and shorter reaction time compared with the wild-type controls in the delayed-matching-to-sample task. The presented data represent the first attempt to experimentally interrogate the genetic basis of human brain origin using a transgenic monkey model and it values the use of non-human primates in understanding unique human traits.
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A transgenic monkey model for the study of human brain evolution.
Why humans have large brains with higher cognitive abilities is a question long asked by scientists. However, much remains unknown, especially the underlying genetic mechanisms. With the use of a transgenic monkey model, we showed that human-specific sequence changes of a key brain development gene (primary microcephaly1, MCPH1) could result in detectable molecular and cognitive changes resembling human neoteny, a notable characteristic developed during human evolution.
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Human neoteny revisited: The case of synaptic plasticity.
The process of learning requires morphological changes in the neuronal connections and the formation of new synapses. Due to the importance of memory and learning in our species, it has been suggested that the synaptic plasticity in a number of association areas is higher in the human brain than in other primates. Cortical neurons in mammals are characterized by higher metabolism, activity, and synaptic plasticity during development and the juvenile stage than in the adult. In Homo sapiens, brain development is retarded compared with other primates, especially in some association areas. These areas are characterized by the presence of neurons, which remain structurally immature throughout their lifespans and show an increase in the expression of the genes, which deal with metabolism and the activity and synaptic plasticity in adulthood. The retention of juvenile features in some adult neurons in our species has occurred in areas, which are related to episodic memory, planning, and social navigation. The increase of the aerobic metabolism in these neurons may lead, however, to higher levels of oxidative stress, therefore, favoring the development of neurodegenerative diseases which are exclusive, or almost exclusive, to humans, such as Alzheimer's disease.