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Olduvai Domains Downregulate Mitochondrial Pathways to Promote Human Brain Evolution and Neoteny.
Olduvai (formerly DUF1220) protein domains, encoded by the NBPF gene family, have undergone the greatest human lineage-specific copy-number expansion of any coding sequence in the genome and strongly correlate with brain size and neuron number across primates. Here we show that Olduvai domains act in a dosage-dependent manner to suppress mitochondrial metabolism. Transcriptomic, proteomic, and live-cell imaging analyses of cells overexpressing NBPF1 (which encodes seven Olduvai domains) reveal pronounced downregulation of mitochondrial pathways, including electron transport chain components and NADH dehydrogenase activity, as well as reduced mitochondrial abundance. By limiting energy availability, this suppression delays cellular maturation and developmental timing. We propose that the resulting prolongation of neurogenesis increases neuron production, providing a mechanistic link between Olduvai copy number expansion and the evolutionary enlargement of the human brain. This dosage-sensitive mitochondrial regulation may also contribute to broader neotenic features of human development, offering a unifying molecular mechanism for brain expansion and the neotenic traits that distinguish humans from other primates.
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Linking mitochondria metabolism, developmental timing, and human brain evolution.
Changes in developmental timing are an important factor of evolution in organ shape and function. This is particularly striking for human brain development, which, compared with other mammals, is considerably prolonged at the level of the cerebral cortex, resulting in brain neoteny. Here, we review recent findings that indicate that mitochondria and metabolism contribute to species differences in the tempo of cortical neuron development. Mitochondria display species-specific developmental timeline and metabolic activity patterns that are highly correlated with the speed of neuron maturation. Enhancing mitochondrial activity in human cortical neurons results in their accelerated maturation, while its reduction leads to decreased maturation rates in mouse neurons. Together with other global and gene-specific mechanisms, mitochondria thus act as a cellular hourglass of neuronal developmental tempo and may thereby contribute to species-specific features of human brain ontogeny.
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How dietary restriction catalyzed the evolution of the human brain: An exposition of the nutritional neurotrophic neoteny theory.
The purpose of this theoretical treatise is to explain the evolution of human encephalization. The evolutionary expansion of the human brain is herein regarded as a single component of an interrelated complex encompassing depressed somatic and sexual development and increased longevity. These cardinal phenotypic features, termed the Quadripartite Complex, were selected for their adaptiveness amidst the environmental deterioration extant during the formative phase of human evolution--the Plio-Pleistocene period. This interval of environmental transformation inevitably eventuated in ecological alteration and dietary diminution. Suggestively, experimentally imposed dietary restriction routinely results in lengthened lifespan, delayed sexual maturation, depressed growth and increased encephalization as a concomitant consequence of body mass reduction and brain mass maintenance. Thus, dietary restriction ostensibly induces discernible metabolic adaptations whether incurred ontologically or evolutionarily. Several experiments indicate that dietary restriction promotes the preservation and generation of neurons via induction of neurotrophic factors. To the extent that neurogenesis is a molecular mediator of mental acuity, it is evident that nutrition and cognition are intimately linked. Extrapolating to an evolutionary context, increased intelligence ought to confer advantages to organisms enduring dietary deprivation insofar as increased intelligence ensures more facile food acquisition. This reasoning underlies the nutritional neurotrophic neoteny (N(3)) theory, which holds that humans exhibit an altered pattern of neurotrophin expression resulting from positive selection for heightened intelligence amidst environmental deterioration and consequent dietary deficiency. The altered pattern of neurotrophin expression exhibited by humans, it is deduced, results in a protracted phase of developmental neurogenesis and a resultant retention of neurons that would otherwise be extirpated due to programmed cell death. Importantly, during neonatal neurogenesis mammals produce an excess number of neurons whose eventual destruction is dictated by neurotrophic factors. An altered pattern of neurotrophin expression during neurogenesis, as N(3) proposes, could therefore furnish a larger adult brain. As to how humans could afford to accrete exuberant neural tissue under conditions of chronic food scarcity the homo hypothalamic hypometabolism (H(3)) theory offers a plausible answer: reduced growth and delayed sexual maturation, mediated by the hypothalamus and its endocrine effectors, offset the energetic costs of increased encephalization in humans. H(3) is herein presented as a general theory of human evolution while N(3) may be regarded as a special theory of human encephalization.
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Evolution and transition of expression trajectory during human brain development.
BACKGROUND: The remarkable abilities of the human brain are distinctive features that set us apart from other animals. However, our understanding of how the brain has changed in the human lineage remains incomplete, but is essential for understanding cognition, behavior, and brain disorders in humans. Here, we compared the expression trajectory in brain development between humans and rhesus macaques (Macaca mulatta) to explore their divergent transcriptome profiles. RESULTS: Results showed that brain development could be divided into two stages, with a demarcation date in a range between 25 and 26 postconception weeks (PCW) for humans and 17-23PCWfor rhesus macaques, rather than birth time that have been widely used as a uniform demarcation time of neurodevelopment across species. Dynamic network biomarker (DNB) analysis revealed that the two demarcation dates were transition phases during brain development, after which the brain transcriptome profiles underwent critical transitions characterized by highly fluctuating DNB molecules. We also found that changes between early and later brain developmental stages (as defined by the demarcation points) were substantially greater in the human brain than in the macaque brain. To explore the molecular mechanism underlying prolonged timing during early human brain development, we carried out expression heterochrony tests. Results demonstrated that compared to macaques, more heterochronic genes exhibited neoteny during early human brain development, consistent with the delayed demarcation time in the human lineage, and proving that neoteny in human brain development could be traced to the prenatal period. We further constructed transcriptional networks to explore the profile of early human brain development and identified the hub gene RBFOX1 as playing an important role in regulating early brain development. We also found RBFOX1 evolved rapidly in its non-coding regions, indicating that this gene played an important role in human brain evolution. Our findings provide evidence that RBFOX1 is a likely key hub gene in early human brain development and evolution. CONCLUSIONS: By comparing gene expression profiles between humans and macaques, we found divergent expression trajectories between the two species, which deepens our understanding of the evolution of the human brain.
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Aerobic glycolysis in the human brain is associated with development and neotenous gene expression.
Aerobic glycolysis (AG; i.e., nonoxidative metabolism of glucose despite the presence of abundant oxygen) accounts for 10%-12% of glucose used by the adult human brain. AG varies regionally in the resting state. Brain AG may support synaptic growth and remodeling; however, data supporting this hypothesis are sparse. Here, we report on investigations on the role of AG in the human brain. Meta-analysis of prior brain glucose and oxygen metabolism studies demonstrates that AG increases during childhood, precisely when synaptic growth rates are highest. In resting adult humans, AG correlates with the persistence of gene expression typical of infancy (transcriptional neoteny). In brain regions with the highest AG, we find increased gene expression related to synapse formation and growth. In contrast, regions high in oxidative glucose metabolism express genes related to mitochondria and synaptic transmission. Our results suggest that brain AG supports developmental processes, particularly those required for synapse formation and growth.
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Loss of Brain Aerobic Glycolysis in Normal Human Aging.
The normal aging human brain experiences global decreases in metabolism, but whether this affects the topography of brain metabolism is unknown. Here we describe PET-based measurements of brain glucose uptake, oxygen utilization, and blood flow in cognitively normal adults from 20 to 82 years of age. Age-related decreases in brain glucose uptake exceed that of oxygen use, resulting in loss of brain aerobic glycolysis (AG). Whereas the topographies of total brain glucose uptake, oxygen utilization, and blood flow remain largely stable with age, brain AG topography changes significantly. Brain regions with high AG in young adults show the greatest change, as do regions with prolonged developmental transcriptional features (i.e., neoteny). The normal aging human brain thus undergoes characteristic metabolic changes, largely driven by global loss and topographic changes in brain AG.
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Brain developmental and cortical connectivity changes in transgenic monkeys carrying the human-specific duplicated gene SRGAP2C.
Human-specific duplicated genes contributed to phenotypic innovations during the origin of our own species, such as an enlarged brain and highly developed cognitive abilities. While prior studies on transgenic mice carrying the human-specific SRGAP2C gene have shown enhanced brain connectivity, the relevance to humans remains unclear due to the significant evolutionary gap between humans and rodents. In this study, to investigate the phenotypic outcome and underlying genetic mechanism of SRGAP2C, we generated transgenic cynomolgus macaques (Macaca fascicularis) carrying the human-specific SRGAP2C gene. Longitudinal MRI imaging revealed delayed brain development with region-specific volume changes, accompanied by altered myelination levels in the temporal and occipital regions. On a cellular level, the transgenic monkeys exhibited increased deep-layer neurons during fetal neurogenesis and delayed synaptic maturation in adolescence. Moreover, transcriptome analysis detected neotenic expression in molecular pathways related to neuron ensheathment, synaptic connections, extracellular matrix and energy metabolism. Cognitively, the transgenic monkeys demonstrated improved motor planning and execution skills. Together, our findings provide new insights into the mechanisms by which the newly evolved gene shapes the unique development and circuitry of the human brain.
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Metabolism Controls the Timing of Human Brain Development and Maturation.
Among primates the human brain is the largest in size, exhibiting a higher neuronal density and connectivity. The prolonged expansion and subsequent connectome reorganization of the human brain have been suggested to promote higher cognitive and behavioral abilities. The notable variations in cognitive functions between human and nonhuman primates do not exclusively reside in neuronal abundance and connectivity but are also linked to a higher complexity in glial cells' morphology and functions at earlier time points, during embryonic brain development. Here we discuss two features of the human brain and their reciprocal connection. One feature is the high metabolic need of the developing and adult human brain. The other is its prolonged maturation, also known as neoteny. Even though the human brain occupies only a small percentage of the body mass, it is the highest consumer of glucose and oxygen. Among all brain cells, neurons have a great energy demand. Comparative studies suggest that increased glucose consumption and energy metabolism are positively correlated with higher cognitive abilities in humans. In line with the essential role of metabolism as a regulator of brain functions, recent breakthrough works have uncovered the correlation between metabolism and the timing of brain and neuron maturation during evolution. In this review, we specifically focus on the role of time in the evolution of the human brain and its synapses, focusing on the involvement of tissue, cellular, and subcellular metabolism.
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Developmental Changes of Human Neural Progenitor Cells Grafted into the Ventricular System and Prefrontal Cortex of Mouse Brain in Utero.
The transplantation of neural progenitors into a host brain represents a useful tool to evaluate the involvement of cell-autonomous processes and host local cues in the regulation of neuronal differentiation during the development of the mammalian brain. Human brain development starts at the embryonic stages, in utero, with unique properties at its neotenic stages. We analyzed the engraftment and differentiation of human neuronal progenitor cells (hNPCs) transplanted in utero into the mouse brain. The influence of the environment was studied by transplanting human NPCs within the lateral ventricles (LV), compared with the prefrontal cortex (PFC) of immunocompetent mice. We developed a semi-automated method to accurately quantify the number of cell bodies and the distribution of neuronal projections among the different mouse brain structures, at 1 and 3 months post-transplantation (MPT). Our data show that human NPCs can differentiate between immature "juvenile" neurons and more mature pyramidal cells in a reproducible manner. Depending on the injection site, LV vs. PFC, specific fetal local environments could modify the synaptogenesis processes while maintaining human neoteny. The use of immunocompetent mice as host species allows us to investigate further neuropathological conditions making use of all of the engineered mouse models already available.
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Neoteny, Prolongation of Youth: From Naked Mole Rats to "Naked Apes" (Humans).
It has been suggested that highly social mammals, such as naked mole rats and humans, are long-lived due to neoteny (the prolongation of youth). In both species, aging cannot operate as a mechanism facilitating natural selection because the pressure of this selection is strongly reduced due to 1) a specific social structure where only the "queen" and her "husband(s)" are involved in reproduction (naked mole rats) or 2) substituting fast technological progress for slow biological evolution (humans). Lists of numerous traits of youth that do not disappear with age in naked mole rats and humans are presented and discussed. A high resistance of naked mole rats to cancer, diabetes, cardiovascular and brain diseases, and many infections explains why their mortality rate is very low and almost age-independent and why their lifespan is more than 30 years, versus 3 years in mice. In young humans, curves of mortality versus age start at extremely low values. However, in the elderly, human mortality strongly increases. High mortality rates in other primates are observed at much younger ages than in humans. The inhibition of the aging process in humans by specific drugs seems to be a promising approach to prolong our healthspan. This might be a way to retard aging, which is already partially accomplished via the natural physiological phenomenon neoteny.