Genetic approaches in mice demonstrate that neuro-mesodermal progenitors express T/Brachyury but not Sox2

Abstract

Neural tube and somites have long been thought to derive from separate germ layers: the ectoderm and mesoderm. This concept was challenged by the discovery of neuromesodermal progenitors, a bi-potent cell population that gives rise to both spinal neural tube and somites. In line with their proposed potency, these cells are considered to co-express the neural marker Sox2 and the mesodermal marker T/Brachyury. We performed genetic lineage tracing in mouse embryos and confirmed that T-expressing cells give rise to both neural tube and mesoderm. Surprisingly, however, Sox2-expressing cell derivatives colonise only the neural tube after embryonic day 8.5. Deletion of Sox2 in T-expressing cells was compatible with an otherwise normal neural tube and paraxial mesoderm. Moreover, Sox2 expression is absent from the chordoneural hinge, where neuro-mesodermal progenitors are located. Our findings demonstrate that neuro-mesodermal progenitors express T but notSox2, suggesting the need for re-evaluation of the neuro-mesodermal progenitor hypothesis.The initial aim of this study was to define the role of NMPs in neural tube formation, since it is not clear to what extent the progenitors contribute to this tissue. We traced cells either from the NSB or CLE into the closing neural tube, and found that the caudal end of the embryo harbours two distinct populations, both of which fulfil the criteria of NMPs, yet give rise to different domains within the closed neural tube. NMP function was addressed using laser ablation and a genetic approach, based on the proposed co-expression of T and Sox2.

Neuromesodermal progenitors separate the axial stem zones while producing few single- and dual-fated descendants

“…What role do the NMP cells play in vivo? Our results show that most cells elongating the axis are born directly in the specialized stem zones (mesodermal and neural), and that the neuromesodermal zone contributes very few cells to either of these; this might explain why their ablation in mouse only produces limited defects (Mugele et al, 2018). It also appears that bipotential progenitors do not actively allocate cells to the specialized axial stem zones based on intrinsic determinants, and do not control the balance of mesoderm and neural tissue produced.…”

“…These could not be directly observed and mapped in mouse (McDole et al, 2018), chick or zebrafish (Attardi et al, 2018) at elongation stages. There is also some controversy regarding their molecular definition and the interpretation of genetic manipulations at population level to deduce the individual cell behaviours fate decisions that allocate cells to the specialised stem zones (Mugele et al, 2018). Here, we used direct, in vivo imaging and comprehensive lineage tracing to determine the relationships between the axial stem zones in the chick.…”

“…However, neither this approach nor extensive lineage reconstruction from live imaging datasets (McDole et al, 2018) could map the NMPs. Molecularly, the neural domain is marked by the expression of Sox2 (Sheng et al, 2003), which marks only neurally-fated cells (Mugele et al, 2018) and is sufficient to neuralise even nascent mesoderm if ectopically expressed (Takemoto et al, 2011). A molecular identity of the MSZ, also committed to its fate, is lacking.…”

“…Pluripotent stem cells from both mouse and human can be induced to co-express this antagonistic set of genes, and produce either mesoderm, neural or neural crest cells (Denham et al, 2015;Frith et al, 2018;Gouti et al, 2014;Lippmann et al, 2015;Tsakiridis et al, 2014;Turner et al, 2014). These suggest that, at population level, cells of neuromesodermal potential correspond to, or are a subset of the Sox2 + , Bra + population, although this definition has recently been challenged (Mugele et al, 2018). The normal fate of bipotent cells could not be established.…”

Cell non-autonomy amplifies disruption of neurulation by mosaic Vangl2 deletion

“…We recently validated an oral tamoxifen administration protocol which robustly activates embryonic CreERT2 without impeding NT closure 46 . Using this method to induce Figure 1B) 47 . In contrast, the neuromesodermal progenitor marker Nkx1.2 CreERT2 lineage traces cells in both ventral PNP and closed NT 48 ( Figure 1A-C).…”