CYCLIN-B1/2 and -D1 act in opposition to coordinate cortical progenitor self-renewal and lineage commitment

Daniel W. Hagey (), Danijal Topcic, Nigel Kee, Florie Reynaud, Maria Bergsland, Thomas Perlmann and Jonas Muhr ()
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Daniel W. Hagey: Karolinska Institutet
Danijal Topcic: Karolinska Institutet
Nigel Kee: Karolinska Institutet
Florie Reynaud: Karolinska Institutet
Maria Bergsland: Karolinska Institutet
Thomas Perlmann: Karolinska Institutet
Jonas Muhr: Karolinska Institutet

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract The sequential generation of layer-specific cortical neurons requires radial glia cells (RGCs) to precisely balance self-renewal and lineage commitment. While specific cell-cycle phases have been associated with these decisions, the mechanisms linking the cell-cycle machinery to cell-fate commitment remain obscure. Using single-cell RNA-sequencing, we find that the strongest transcriptional signature defining multipotent RGCs is that of G2/M-phase, and particularly CYCLIN-B1/2, while lineage-committed progenitors are enriched in G1/S-phase genes, including CYCLIN-D1. These data also reveal cell-surface markers that allow us to isolate RGCs and lineage-committed progenitors, and functionally confirm the relationship between cell-cycle phase enrichment and cell fate competence. Finally, we use cortical electroporation to demonstrate that CYCLIN-B1/2 cooperate with CDK1 to maintain uncommitted RGCs by activating the NOTCH pathway, and that CYCLIN-D1 promotes differentiation. Thus, this work establishes that cell-cycle phase-specific regulators act in opposition to coordinate the self-renewal and lineage commitment of RGCs via core stem cell regulatory pathways.

Date: 2020
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DOI: 10.1038/s41467-020-16597-8

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