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Species-Specific miRNAs in Human Brain Development and Disease


Species-Specific miRNAs in Human Brain Development and Disease

Kanella Prodromidou et al. Front Cell Neurosci.


Identification of the unique features of human brain development and function can be critical towards the elucidation of intricate processes such as higher cognitive functions and human-specific pathologies like neuropsychiatric and behavioral disorders. The developing primate and human central nervous system (CNS) are distinguished by expanded progenitor zones and a protracted time course of neurogenesis, leading to the expansion in brain size, prominent gyral anatomy, distinctive synaptic properties, and complex neural circuits. Comparative genomic studies have revealed that adaptations of brain capacities may be partly explained by human-specific genetic changes that impact the function of proteins associated with neocortical expansion, synaptic function, and language development. However, the formation of complex gene networks may be most relevant for brain evolution. Indeed, recent studies identified distinct human-specific gene expression patterns across developmental time occurring in brain regions linked to cognition. Interestingly, such modules show species-specific divergence and are enriched in genes associated with neuronal development and synapse formation whilst also being implicated in neuropsychiatric diseases. microRNAs represent a powerful component of gene-regulatory networks by promoting spatiotemporal post-transcriptional control of gene expression in the human and primate brain. It has also been suggested that the divergence in miRNA expression plays an important role in shaping gene expression divergence among species. Primate-specific and human-specific miRNAs are principally involved in progenitor proliferation and neurogenic processes but also associate with human cognition, and neurological disorders. Human embryonic or induced pluripotent stem cells and brain organoids, permitting experimental access to neural cells and differentiation stages that are otherwise difficult or impossible to reach in humans, are an essential means for studying species-specific brain miRNAs. Single-cell sequencing approaches can further decode refined miRNA-mRNA interactions during developmental transitions. Elucidating species-specific miRNA regulation will shed new light into the mechanisms that control spatiotemporal events during human brain development and disease, an important step towards fostering novel, holistic and effective therapeutic approaches for neural disorders. In this review, we discuss species-specific regulation of miRNA function, its contribution to the evolving features of the human brain and in neurological disease, with respect also to future therapeutic approaches.

Keywords: RNA sequencing (RNAseq); brain; evolution; gene networks; human; miRNAs; neurogenesis; primate.


Figure 1
Figure 1
Species-specific evolution of traits associated with brain development during the divergence to primate and human lineages. Although brain development follows the same basic principles across mammals, evolution has resulted in the appearance of species-specific features. Characteristics of primate divergence include allometric increase in brain size, expansion of progenitor zones along with increased diversity of neural cell types and sophistication of neural circuits reflected in enhanced gyral anatomy. Human brain development is further distinguished by a relatively protracted period of neurogenesis, followed by an extraordinary numeric expansion of the neuronal cell population and by the heterochronic or heterotopic expression of genes associated with synapse formation and myelination in brain regions including the prefrontal cortex, which is central to human cognition and behavior.
Figure 2
Figure 2
miRNAs shape gene networks during the evolution of human and non-human primate brain development. Transcriptomic studies show that miRNA-mediated regulation during primate brain evolution contributed critically in shaping gene networks associated with progenitor proliferation, neuronal differentiation, and acquisition of cell identities, an extension of neuronal processes, regional specialization and neurodevelopmental disorders as depicted on the petals. A limited number of primate- or human-specific miRNAs are indicated next to the petals, for which separate studies exist so far to demonstrate their individual involvement in the respective biological processes.

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    1. Adams D., Gonzalez-Duarte A., O’Riordan W. D., Yang C. C., Ueda M., Kristen A. V., et al. . (2018). Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 11–21. 10.1056/NEJMoa1716153 - DOI - PubMed
    1. Adlakha Y. K., Saini N. (2014). Brain microRNAs and insights into biological functions and therapeutic potential of brain enriched miRNA-128. Mol. Cancer 13:33. 10.1186/1476-4598-13-33 - DOI - PMC - PubMed
    1. Allman J. M., Tetreault N. A., Hakeem A. Y., Manaye K. F., Semendeferi K., Erwin J. M., et al. . (2010). The von Economo neurons in frontoinsular and anterior cingulate cortex in great apes and humans. Brain Struct. Funct. 214, 495–517. 10.1007/s00429-010-0254-0 - DOI - PubMed
    1. Ameres S. L., Horwich M. D., Hung J. H., Xu J., Ghildiyal M., Weng Z., et al. . (2010). Target RNA-directed trimming and tailing of small silencing RNAs. Science 328, 1534–1539. 10.1126/science.1187058 - DOI - PMC - PubMed
    1. Arcila M. L., Betizeau M., Cambronne X. A., Guzman E., Doerflinger N., Bouhallier F., et al. . (2014). Novel primate miRNAs coevolved with ancient target genes in germinal zone-specific expression patterns. Neuron 81, 1255–1262. 10.1016/j.neuron.2014.01.017 - DOI - PMC - PubMed

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