Co-expression of Tbx6 and Sox2 identifies a novel transient neuromesoderm progenitor cell state

Abstract

Elongation of the body axis is a key aspect of body plan development. Bipotential neuromesoderm progenitors (NMPs) ensure axial growth of embryos by contributing both to the spinal cord and mesoderm. The current model for the mechanism controlling NMP deployment invokes Tbx6, a T-box factor, to drive mesoderm differentiation of NMPs. Here, we identify a new population of Tbx6 cells in a subdomain of the NMP niche in mouse embryos. Based on co-expression of a progenitor marker, Sox2, we identify this population as representing a transient cell state in the mesoderm-fated NMP lineage. Genetic lineage tracing confirms the presence of the NMP cell state. Furthermore, we report a novel aspect of the documented mutant phenotype, namely an increase from two to four ectopic neural tubes, corresponding to the switch in NMP niche, thus highlighting the importance of function in NMP fate decision. This study emphasizes the function of Tbx6 as a bistable switch that turns mesoderm fate 'on' and progenitor state 'off', and thus has implications for the molecular mechanism driving NMP fate choice.

Human axial progenitors generate trunk neural crest cells

“…Specifically, trunk NC production has been shown to be controlled by transcription factors which also regulate cell fate decisions in axial progenitors such as CDX proteins (45-47) and NKX1-2 (48). The close relationship between bipotent axial and posterior NC progenitors is further supported by fate mapping experiments involving the grafting of a portion of E8.5 mouse caudal lateral epiblast T+SOX2+ cells (27) and avian embryonic TB regions (22, 34) as well as lineage tracing experiments (23, 24) which have revealed the presence of cell populations exhibiting simultaneously mesodermal, neural and NC differentiation potential. Together these findings suggest that the trunk/lumbar NC is likely to originate from a subset of axial progenitors arising near the PS/TB.…”

“…No unique NMP markers have been determined to date and thus phenotypically NMPs are defined by the co-expression of the pro-mesodermal transcription factor Brachyury (T) and neural regulator SOX2 (35-37). Furthermore, they express transcripts which are also present in the primitive streak (PS) and TB marking committed PXM and posterior neurectodermal progenitors such as Cdx and Hox gene family members, Tbx6 and Nkx1-2 (23, 24, 31, 38, 39). T and SOX2 have a critical role, in conjunction with CDX and HOX proteins, in regulating the balance between NMP maintenance and differentiation by integrating inputs predominantly from the WNT and FGF signalling pathways (27, 38-41).…”

Sall4 regulates neuromesodermal progenitors and their descendants during body elongation in mouse embryos

“…During the fate choice between neural and PM progenitors, defects in the WNT/β-catenin-T regulatory loop cause expansion of neural tissues and reduction of PM, suggesting that WNT/ β-catenin signaling promotes NMP differentiation toward the mesodermal lineage (Garriock et al, 2015;Martin and Kimelman, 2012). The WNT/β-catenin-T loop regulates another T-box gene, Tbx6, which functions in early fate choice of NMPs into mesoderm (Javali et al, 2017;Koch et al, 2017;Nowotschin et al, 2012;Takemoto et al, 2011). In contrast, retinoic acid plays a role in promoting differentiation into neural fate (Cunningham et al, 2016;Gouti et al, 2017).…”

Position-sensing established during compaction dictates cell fate in the mammalian embryo

“…Information about geometry (sphericity, surface area, volume, oblate and prolate) and signal intensity within each compartment could then be exported. Information about blastomere exposed, contact and junctional surface areas was obtained by considering surface proximities and was automated using an in-house developed software (Javali et al, 2017;Leonavicius et al, 2017). Signal intensity around these defined membrane domains could then be extracted.…”