Neuromesodermal Progenitors are a Conserved Source of Spinal Cord with Divergent Growth Dynamics

Abstract

Abstract:2 During gastrulation, embryonic cells become specified into distinct germ layers. In mouse, 15All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Sox2 and Canonical Wnt Signaling Interact to Activate a Developmental Checkpoint Coordinating Morphogenesis with Mesoderm Fate Acquisition

“…Here, we show that lowering the level of Wnt signaling can recapitulate the mouse Tbx6 ectopic spinal cord phenotype in zebrafish tbx16 mutants. One implication of this result is that the relative amount of Wnt signaling is higher in the zebrafish tailbud compared to the mouse, which may help explain the species-specific differences between NMP development (Martin and Kimelman, 2009;Steventon et al, 2016;Attardi et al, 2018;Mallo, 2020), including the phenotypic differences of the Tbx6 mouse mutant and the tbx16 single or tbx16/tbx6l and tbx16/msgn1 double zebrafish mutants (Chapman and Papaioannou, 1998;Fior et al, 2012;Yabe and Takada, 2012;Morrow et al, 2017).…”

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

“…Indeed, these studies revealed the existence of single progenitors able to give rise to only neural or mesodermal cells but also pointed out to the existence of a third type of progenitor able to generate both neural and mesodermal cells. These bi-potential progenitors, named neuro-mesodermal progenitors (NMPs), have later been shown to exist in zebrafish (10) and in bird embryos (48,50,51). In the early bird embryo (stage HH4-7), the future posterior progenitors are initially located in anterior epithelial structures: the epiblast and the primitive streak.…”

Is it possible to reconstruct an accurate cell lineage using CRISPR recorders?

“…The use of CRISPR-induced somatic mutations is emerging as an attractive approach for reconstructing complex cell lineages. A variety of CRISPR-based lineage recorders has been developed to test this approach (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). If the results of these methods are to be useful for gaining biological insights, however, it is essential that the inferred lineage trees are sufficiently reliable, i.e.…”

“…The problem of dropouts could be reduced by opting for the lower end of the optimal range of mutation rates; or eliminated by targeting separate loci in the genome rather than arrays of targets. Available implementations of CRISPR type recorders are based on different conceptual designs: barcoded arrays recording point mutations (5,12), "collapsing" arrays (6), targets distributed in different genomic locations (7,10,11,13,14) and mutations induced by self-targeting guide RNAs (8,9). Here we have simulated the first two types of recorders, but we expect that the insights that we have gained on the importance of optimising mutation rates, target numbers and the complexity of character states will apply to all types of recorders.…”

“…While this approach is theoretically possible (3), it is nevertheless limited by the enormous challenge of detecting these rare mutations within the genomes of individual cells. As a solution to the problem of reading the mutations, several recent papers have explored the idea of using CRISPRinduced somatic mutations, targeted to artificial sequences inserted as transgenes into the genome (termed "CRISPR recorders") (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The recorders consist of arrays of CRISPR target sites, targeted by their cognate sgRNAs and Cas9 during development.…”