Medevielle, F. | bioRxiv Science

bioRxiv2021

Control of G2 phase duration by CDC25B modulates the switch from direct to indirect neurogenesis in the neocortex

During development, cortical neurons are produced in a temporally regulated sequence from apical progenitors, directly, or indirectly through the production of intermediate basal progenitors. The balance between these major progenitors types is determinant for the production of the proper number and types of neurons and it is thus important to decipher the cellular and molecular cues controlling this equilibrium. Here we address the role of a cell cycle regulator, the CDC25B phosphatase, in this process. We show that deleting CDC25B in apical progenitors leads to a transient increase of the production of TBR1+ neurons at the expense of TBR2+ basal progenitors in mouse neocortex. This phenotype is associated with lengthening of the G2 phase of the cell cycle, the total cell cycle length being unaffected. Using in utero electroporation and cortical slice cultures, we demonstrate that the defect in TBR2+ basal progenitor production requires interaction with CDK1 and is due to the G2 phase lengthening in CDC25B mutants. Altogether, this study identifies a new role for CDC25B and the length of the G2 phase in direct versus indirect neurogenesis at early stages of the cortical development.

developmental biology↗

bioRxiv2020

Cell-to-cell heterogeneity in Sox2 and Brachyury expression guides progenitor destiny by controllingtheir movements.

Although cell-to-cell heterogeneity in gene and protein expression within cell populations has been widely documented, we know little about its potential biological functions. We addressed this issue by studying progenitors that populate the posterior region of the vertebrate embryos, a cell population known for its capacity to self-renew or to contribute to the formation of the neural tube and paraxial mesoderm tissues. Posterior progenitors are characterized by the co-expression of Sox2 and Brachyury (Bra), two transcription factors related to neural and mesodermal lineages, respectively. In this study, we show that the respective levels of Sox2 and Bra proteins display a high degree of variability among posterior progenitors of the quail embryo. By developing forced expression and downregulation approaches, we further provide evidence that the value of the Sox2-to-Bra ratio in a given progenitor directs its choice of staying in place or exit the progenitor zone to generate neural or mesodermal cells. Time-lapse imaging together with mathematical modeling then reveal that variations of the Sox2-to-Bra ratio confer these cells heterogeneous motile behaviors. While high Bra levels display high motile properties that push cells to join the mesoderm, high levels of Sox2 tend to inhibit cell movement making cells get integrated into the neural tube. Our work thus provides evidence that the spatial heterogeneity of posterior progenitors, with regards to their relative contents of Sox2 and Bra and thus to their motile properties, is fundamental to maintain a pool of resident progenitors while others segregate to contribute to tissue formation. More broadly, our work reveals that heterogeneity among a population of progenitor cells is critical to ensure robust multi-tissue morphogenesis.

developmental biology↗