Cell-to-cell heterogeneity in Sox2 and Brachyury expression ratios guides progenitor destiny by controlling their motility.

Abstract

Although cell-to-cell heterogeneity in gene and protein expression has been widely documented within a given cell population, little is known about its potential biological functions. We addressed this issue by studying posterior progenitors, an embryonic cell population that is central to vertebrate posterior axis formation. These progenitors are able to maintain themselves within the posterior region of the embryo or to exit this region to participate in the formation of neural tube or paraxial mesoderm tissues. Posterior progenitors are known to co-express transcription factors related to neural and mesodermal lineages, e.g. Sox2 and Brachyury (Bra), respectively. In this study, we find that expression levels of Sox2 and Bra proteins display a high degree of variability among posterior progenitors of the quail embryo, therefore highlighting spatial heterogeneity of this cell population. By over-expression/down-regulation experiments and time-lapse imaging, we show that Sox2 and Bra are both involved in controlling progenitor motility, acting however in an opposite way: while Bra is necessary to progenitor motion, Sox2 tends to inhibit cell movement. Combining mathematical modeling and experimental approaches, we provide evidence that the spatial heterogeneity of posterior progenitors, with regards to their expression levels 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. As a whole, our work reveals that heterogeneity among a population of progenitor cells is critical to ensure robust multi-tissue morphogenesis.

Cell Lineage, Self-Renewal, and Epithelial-to-Mesenchymal Transition during Secondary Neurulation

“…It raises an interesting possibility that the lineage of mesodermal cells is different between the trunk and tail: in the trunk, mesodermal cells are produced through the primitive streak by EMT, whereas those in the tail derive by re-direction of originally SN uni-fated precursors. This idea agrees, although partly, with the concept of neuro-mesodermal progenitors (NMPs) [ 10 , 19 , 21 ]. A currently prevailing model of NMPs is that axial progenitor cells are neuro- and mesodermal common progenitors.…”

Stem Cell Neurodevelopmental Solutions for Restorative Treatments of the Human Trunk and Spine

“…Both models produce the spinal cord and paraxial mesoderm/somites from caudal stem cell pools. SOX2/Bra spatial heterogeneity in NMPs correlates with differential migratory velocity and PSM vs. spinal cord lineage commitment (Romanos et al, 2021 ). NCC, neural crest cell; aPSM/pPSM, anterior/posterior presomitic mesoderm; PNS, peripheral nervous system; CNS, central nervous system.…”

“…This may contribute to neural cell fate commitment with precisely defined positional identity along the rostral-caudal neuraxis during elongation (Diez del Corral et al, 2003 ; Lippmann et al, 2015 ). In a new study, it was shown that the NMP population comprising the progenitor zone is spatially heterogenous with differential stochastic expression of SOX2 vs. Bra (Romanos et al, 2021 ). By in silico modeling and in vivo validation of the model in quail embryos, it was shown that higher SOX2 expression biases to spinal cord fate while higher Bra expression biases to PSM, where PSM-biased cells have higher migration rates vs. SOX2-biased cells ( Figure 2C ).…”

In vitro systems: A new window to the segmentation clock

“…In mouse and chicken embryos, paraxial mesoderm is derived from a population of precursor cells in the anterior region of the primitive streak and its lateral epiblast (Figure 3a). This region contains lineage‐restricted progenitors as well as neuromesodermal progenitors (NMPs) (Guillot et al, 2020; Iimura et al, 2007; Romanos et al, 2020; Tzouanacou et al, 2009). Even though NMPs have only been recently described and remain to be fully characterized, they can be defined as transcriptionally distinct progenitor cells that have the potential to give rise to both paraxial mesoderm and neural tube lineages (Wilson et al., 2009).…”

“…NMPs are commonly identified by the co‐expression of the mesodermal marker T/Brachyury and the neural marker Sox2 (Henrique et al, 2015 ) . However, levels of SOX2 and T vary between progenitor cells and can bias the differentiation potential of these cells towards the mesodermal or neural lineage (Kawachi et al, 2020; Romanos et al, 2020). Furthermore, even though NMPs have been described in vivo in zebrafish, chicken, and mouse embryos, the degree of evolutionary conservation of this cell type remains poorly understood (Attardi, 2018; Guillot et al, 2020; Tzouanacou et al, 2009).…”