Abstract
The development of the central nervous system is known to result from two sequential events. First, an inductive event of the mesoderm on the overlying ectoderm that generates a neural plate that, after rolling into a neural tube, acts as the main source of neural progenitors. Second, the axial regionalization of the neural plate that will result in the specification of neurons with different anteroposterior identities. Although this description of the process applies with ease to amphibians and fish, it is more difficult to confirm in amniote embryos. Here, a specialized population of cells emerges at the end of gastrulation that, under the influence of Wnt and FGF signalling, expands and generates the spinal cord and the paraxial mesoderm. This population is known as the long-term neuromesodermal precursor (NMp). Here, we show that controlled increases of Wnt/β-catenin and FGF signalling during adherent culture differentiation of mouse embryonic stem cells (mESCs) generates a population with many of the properties of the NMp. A single-cell analysis of gene expression within this population reveals signatures that are characteristic of stem cell populations. Furthermore, when this activation is triggered in three-dimensional aggregates of mESCs, the population self-organizes macroscopically and undergoes growth and axial elongation that mimics some of the features of the embryonic spinal cord and paraxial mesoderm. We use both adherent and three-dimensional cultures of mESCs to probe the establishment and maintenance of NMps and their differentiation.
Highlights
The nervous system comprises a cellular network that processes sensory and motor information to generate patterns of activity and behaviour in the organism
Using a recently developed 3D culture system of mouse embryonic stem cells (mESCs) (Baillie-Johnson et al, 2014; van den Brink et al, 2014), we show that a similar treatment of cell aggregates results in the emergence of a directional extension that is neural in character and harbours, at its distal end, a population that resembles the neuromesodermal precursor (NMp) in terms of gene expression and phenotypic behaviour
Wnt/β-catenin signalling promotes the emergence of posterior axial fates in adherent mESC differentiation In the postimplantation epiblast of the mouse embryo, cells become allocated to one of two prospective fates: anterior neuroectoderm that will give rise to the anterior nervous system; or, posteriorly, to a rapidly expanding population that gives rise to the mesoderm and the endoderm through the primitive streak (Arnold and Robertson, 2009; Rossant and Tam, 2009)
Summary
The nervous system comprises a cellular network that processes sensory and motor information to generate patterns of activity and behaviour in the organism. The basic framework of the network is engineered during development from a sheet of neuroepithelial progenitors that arise in an anteroposterior sequence as the body plan unfolds. This process can be followed through the expression of members of the Sox2b. Experiments with Xenopus animal caps showed that the inductive event is associated with an antagonism of BMP signalling and, by extension, that BMP acts as a pan-neural repressor across the ectoderm (Hemmati-Brivanlou and Melton, 1997a). Expression of the BMP antagonists chordin, noggin and follistatin from the organizer releases this repression locally and allows the dynamic emergence of neural progenitors (reviewed by Hemmati-Brivanlou and Melton, 1997b; De Robertis et al, 2001). The notion that BMP antagonism is the main mechanism of neural induction has been challenged; in particular, it has been suggested that other signalling pathways, FGF/ERK and Wnt, are involved in the acquisition of the neural fate independently of the inhibition of BMP (Stern, 2005)
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