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  • Review Article
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Indirect neurogenesis in space and time

Abstract

During central nervous system (CNS) development, neural progenitor cells (NPCs) generate neurons and glia in two different ways. In direct neurogenesis, daughter cells differentiate directly into neurons or glia, whereas in indirect neurogenesis, neurons or glia are generated after one or more daughter cell divisions. Intriguingly, indirect neurogenesis is not stochastically deployed and plays instructive roles during CNS development: increased generation of cells from specific lineages; increased generation of early or late-born cell types within a lineage; and increased cell diversification. Increased indirect neurogenesis might contribute to the anterior CNS expansion evident throughout the Bilateria and help to modify brain-region size without requiring increased NPC numbers or extended neurogenesis. Increased indirect neurogenesis could be an evolutionary driver of the gyrencephalic (that is, folded) cortex that emerged during mammalian evolution and might even have increased during hominid evolution. Thus, selection of indirect versus direct neurogenesis provides a powerful developmental and evolutionary instrument that drives not only the evolution of CNS complexity but also brain expansion and modulation of brain-region size, and thereby the evolution of increasingly advanced cognitive abilities. This Review describes indirect neurogenesis in several model species and humans, and highlights some of the molecular genetic mechanisms that control this important process.

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Fig. 1: Indirect neurogenesis modulates key aspects of neural development.
Fig. 2: Drosophila embryos display a gradient of indirect neurogenesis that results in a corresponding gradient in average lineage size.
Fig. 3: Brain region-specific modulation of indirect neurogenesis can result in region-specific changes in size.
Fig. 4: Evolutionary increase in indirect neurogenesis in the vertebrate developing neocortex.

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Acknowledgements

S.T. thanks S. Temple, H. Wang, L. Fenlon and C. Q. Doe for advice or comments on the manuscript, and A. Kallstrand Thor for help with the illustrations.

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Correspondence to Stefan Thor.

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S.T. has received research grants from the Australian Research Council (DP220100985, DP230101750), the Australian National Health and Medical Research Council (230101750) and The University of Queensland, Australia.

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Thor, S. Indirect neurogenesis in space and time. Nat. Rev. Neurosci. 25, 519–534 (2024). https://doi.org/10.1038/s41583-024-00833-x

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