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How mechanisms of stem cell polarity shape the human cerebral cortex

Nature Reviews Neuroscience volume 23, pages 711–724 (2022)Cite this article

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Abstract

Apical–basal progenitor cell polarity establishes key features of the radial and laminar architecture of the developing human cortex. The unique diversity of cortical stem cell populations and an expansion of progenitor population size in the human cortex have been mirrored by an increase in the complexity of cellular processes that regulate stem cell morphology and behaviour, including their polarity. The study of human cells in primary tissue samples and human stem cell-derived model systems (such as cortical organoids) has provided insight into these processes, revealing that protein complexes regulate progenitor polarity by controlling cell membrane adherence within appropriate cortical niches and are themselves regulated by cytoskeletal proteins, signalling molecules and receptors, and cellular organelles. Studies exploring how cortical stem cell polarity is established and maintained are key for understanding the features of human brain development and have implications for neurological dysfunction.

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Fig. 1: Progenitor types and division programmes in the developing human cortex.
Fig. 2: Subcellular structures and organelles regulating progenitor polarity.
Fig. 3: Human-specific regulation of the cytoskeleton in outer radial glial cells.

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Acknowledgements

The authors thank members of the Kriegstein laboratory for invaluable discussions about human cortical development. This article was supported by National Institutes of Health (NIH) awards U01MH114825 and R35NS097305 to A.R.K. and K99MH125329 to M.G.A., and a Brain & Behaviour Research Foundation Young Investigator Grant to M.G.A.

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Author notes

  1. These authors contributed equally: Madeline G. Andrews, Lakshmi Subramanian.

Authors and Affiliations

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

    Madeline G. Andrews, Lakshmi Subramanian & Arnold R. Kriegstein

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

    Madeline G. Andrews, Lakshmi Subramanian & Arnold R. Kriegstein

  3. School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA

    Madeline G. Andrews

  4. Department of Pharmacology, Ideaya Biosciences, South San Francisco, CA, USA

    Lakshmi Subramanian

  5. Centre for Regenerative Medicine and Stem Cell Research, The Aga Khan University, Karachi, Pakistan

    Jahan Salma

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M.G.A., L.S. and J.S. researched data for the article and wrote the article. All authors contributed substantially to discussion of content and reviewed and/or edited the manuscript before submission.

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Correspondence to Arnold R. Kriegstein.

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A.R.K. is a co-founder, consultant and member of the Board of Neurona Therapeutics. The other authors declare no competing interests.

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Glossary

Stem cells

A collective term for neuroepithelial cells and radial glial cells; multipotent cells that give rise to other progenitor cells and various neuronal and glial cell types.

Progenitor cells

Multipotent cells (such as intermediate progenitor cells) that differentiate into postmitotic cell types.

Neuroepithelial cells

Pseudostratified stem cells that establish the developing neocortex through their polar morphology.

Cell cycle

A process of cell division, in which one cell becomes two; composed of stages that include cell growth (G1 phase, G2 phase), DNA synthesis (S phase) and mitosis/cytokinesis (M phase).

Symmetric division

Cell division in which a parent cell gives rise to two identical daughter cells. This type of division can be self-renewing.

Radial glial scaffold

A structure in the developing cerebral cortex that has an apical–basal orientation and is composed of the basal processes of radial glial cells. The scaffold is required to support neurons as they migrate through the developing cortex to reach their laminar position. Progenitor polarity is essential for scaffold integrity.

Ventricular zone

(VZ). A progenitor zone located on the apical side of the developing cortex in close proximity to the lateral ventricle. The VZ is usually defined as the zone of interkinetic nuclear migration of radial glia.

Asymmetric division

Cell division in which a parent cell gives rise to two different daughter cells. This can be a differentiating division.

Horizontal divisions

Cell divisions in which there is a horizontal plane of cytokinesis. These divisions are typically asymmetric.

Pluripotent stem cell

(PSC). A cell that has the potential to become any other cell type in the body. There are two types of PSC: embryonic stem cells are derived from the inner cell mass of blastocyst and induced PSCs are reprogrammed from somatic cells.

Cerebral organoids

Three-dimensional neural structures resembling the developing cerebrum that spontaneously differentiate from pluripotent stem cells without manipulation of developmental signalling molecules.

Primary cilium

A slim microtubule-based organelle that is present in most eukaryotic cells. The primary cilium is made up of nine microtubule bundles (called an axoneme) and has a ciliary membrane. In neuroepithelial cells and radial glial cells, the primary cilia extend into the ventricular space.

Macrocephaly

A cortical malformation in which the cortex is larger than normal, identified by an increase in head circumference.

Microcephaly

A cortical malformation in which the cortex is smaller than normal.

Delamination

A process in which epithelial cells lose contact with their neighbours and move out of the epithelial sheet. In the developing cerebral cortex, this occurs when neuroepithelial cells and radial glial cells lose junctional contacts and/or retract their cellular processes and then migrate into a different position in the developing cortex.

Cerebrospinal fluid

(CSF). A fluid that contains the necessary nutrients for brain health. CSF is produced by the choroid plexus and flows through the ventricles. During development, radial glial apical and basal endfeet are exposed to CSF.

Developmental niches

Uniquely defined extracellular micro-environments that are clearly distinguished from other parts of the cortex.

Gyrencephaly

The characteristic folding of the cerebral cortex, resulting in increased cortical surface area.

Megalencephaly

A cortical malformation in which the brain is atypically large or heavy, defined by an increase in brain tissue.

Lissencephaly

A cortical malformation in which the brain is smooth and does not have appropriate gyrification.

Heterotopias

Cortical malformations in which neural cells are in the incorrect position.

Centrosome

A cellular structure that comprises microtubules and is involved in cell division.

Deep-layer neurons

Subcortically projecting excitatory neurons that reside in cortical layers V and VI.

Hydrocephalus

A condition in which there is increased cerebrospinal fluid volume in the ventricles.

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Andrews, M.G., Subramanian, L., Salma, J. et al. How mechanisms of stem cell polarity shape the human cerebral cortex. Nat Rev Neurosci 23, 711–724 (2022). https://doi.org/10.1038/s41583-022-00631-3

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