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Human neuronal maturation comes of age: cellular mechanisms and species differences

Nature Reviews Neuroscience volume 25, pages 7–29 (2024)Cite this article

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Abstract

The delayed and prolonged postmitotic maturation of human neurons, compared with neurons from other species, may contribute to human-specific cognitive abilities and neurological disorders. Here we review the mechanisms of neuronal maturation, applying lessons from model systems to understand the specific features of protracted human cortical maturation and species differences. We cover cell-intrinsic features of neuronal maturation, including transcriptional, epigenetic and metabolic mechanisms, as well as cell-extrinsic features, including the roles of activity and synapses, the actions of glial cells and the contribution of the extracellular matrix. We discuss evidence for species differences in biochemical reaction rates, the proposed existence of an epigenetic maturation clock and the contributions of both general and modular mechanisms to species-specific maturation timing. Finally, we suggest approaches to measure, improve and accelerate the maturation of human neurons in culture, examine crosstalk and interactions among these different aspects of maturation and propose conceptual models to guide future studies.

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Fig. 1: Neuronal development and maturation across species.
Fig. 2: Cell-intrinsic and cell-extrinsic mechanisms of neuronal maturation.
Fig. 3: Mechanisms that contribute to evolutionary differences in neuronal maturation rates.
Fig. 4: The flow of neuronal maturation.

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Acknowledgements

The authors acknowledge C. Chen, S. Nolbrant, B. Pavlovic and A. Sousa for helpful discussions and comments on the manuscript and funding from the following funding sources: Jane Coffin Childs (J.L.W.), Schmidt Science Fellows (J.L.W.), US National Institutes of Health DP2MH122400-01 (A.A.P.) and Schmidt Futures Foundation (A.A.P.). A.A.P. is a New York Stem Cell Foundation Robertson Investigator.

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Authors and Affiliations

  1. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA

    Jenelle L. Wallace & Alex A. Pollen

  2. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA

    Jenelle L. Wallace & Alex A. Pollen

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  1. Jenelle L. Wallace
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All authors researched data for the article, contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. J.L.W. wrote the article.

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Supplementary information

Glossary

Activity-regulated genes

Genes whose expression levels are regulated by levels or patterns of neuronal activity. These include a first wave of early response genes (also known as immediate early genes) and a second wave of late response genes.

Bivalent promoters

Promoters whose surrounding histones bear both active H3K4me2/3 (di- or trimethylation of histone 3 lysine 4) and repressive H3K27me3 (trimethylation of histone 3 lysine 27) marks, thought to prepare the expression of genes that are turned on at later developmental timepoints.

Cell-extrinsic factors

Factors that originate externally to a cell (components of the environment) and that influence the properties or responses of the cell.

Cell-intrinsic factors

Factors that originate from within a cell and are preserved even when the cell is removed from its native environment.

Chromatin

A complex found in the nucleus of a cell that comprises DNA and associated proteins that organize, package and regulate DNA replication and gene expression.

cis-regulatory mechanisms

Mechanisms in which cis-regulatory elements control the expression of individual genes nearby on the chromosome.

Cortical plate

Term for nascent cortical layers II–VI during embryonic development before the laminar cytoarchitecture becomes distinct.

Enhancers

Genomic elements distal to gene promoters that regulate gene expression levels and/or probability; an example of cis-regulatory elements.

Glycolysis

A metabolic pathway that takes place in the cytoplasm in which cells produce ATP and lactate/pyruvate, which may be processed further by oxidative phosphorylation. This pathway is less efficient for ATP production than oxidative phosphorylation.

Heterochrony

Evolutionary changes in developmental timing.

Histone modifications

Chemical alterations (including acetylation and methylation) of the amino acids in histone proteins, which regulate gene expression and chromatin compaction.

Multimodal methods

Methods for cellular characterization that combine two or more methods from different categories (for example, molecular, structural, functional and metabolic).

Neotenous

Exhibits retention of juvenile characteristics in a sexually mature adult.

Neuronal maturation

The process by which postmitotic neurons undergo molecular, metabolic, morphological and functional changes; engage in cellular interactions (including the establishment of synaptic connectivity and myelination); and achieve a steady-state phenotype in the adult brain.

Nucleosomes

Protein complexes that each contain eight histones, around which DNA is coiled.

Oxidative phosphorylation

(OXPHOS). A metabolic pathway that takes place in mitochondria in which cells use products of glucose metabolism and oxygen to produce energy in the form of ATP.

Subplate

A transient layer of neurons located between the proliferative zone and the cortical plate. The subplate mostly disappears before birth, owing to cell migration and apoptosis, and the remaining cells become layer VIb neurons.

Topologically associating domains

(TADs). Units of genome organization in which there are higher levels of chromatin interaction internally than externally, demarcating boundaries of looping interactions between enhancers and promoters.

Transcription factors

Proteins that bind to DNA at enhancers and/or promoters to regulate gene expression; an example of trans-regulation.

trans-regulatory mechanisms

Mechanisms in which trans-regulatory factors coordinate the activity of large suites of genes.

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Wallace, J.L., Pollen, A.A. Human neuronal maturation comes of age: cellular mechanisms and species differences. Nat. Rev. Neurosci. 25, 7–29 (2024). https://doi.org/10.1038/s41583-023-00760-3

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