Specification and maintenance of the spinal cord stem zone

Abstract

Epiblast cells adjacent to the regressing primitive streak behave as a stem zone that progressively generates the entire spinal cord and also contributes to paraxial mesoderm. Despite this fundamental task, this cell population is poorly characterised, and the tissue interactions and signalling pathways that specify this unique region are unknown. Fibroblast growth factor (FGF) is implicated but it is unclear whether it is sufficient and/or directly required for stem zone specification. It is also not understood how establishment of the stem zone relates to the acquisition of spinal cord identity as indicated by expression of caudal Hox genes. Here, we show that many cells in the chick stem zone express both early neural and mesodermal genes; however, stem zone-specific gene expression can be induced by signals from underlying paraxial mesoderm without concomitant induction of an ambivalent neural/mesodermal cell state. The stem zone is a site of FGF/MAPK signalling and we show that although FGF alone does not mimic paraxial mesoderm signals, it is directly required in epiblast cells for stem zone specification and maintenance. We further demonstrate that caudal Hox gene expression in the stem zone also depends on FGF and that neither stem zone specification nor caudal Hox gene onset requires retinoid signalling. These findings thus support a two step model for spinal cord generation -FGF-dependent establishment of the stem zone in which progressively more caudal Hox genes are expressed, followed by the retinoid-dependent assignment of spinal cord identity.

Morphogens and the Control of Cell Proliferation and Patterning in the Spinal Cord

“…FGF signaling is required for expression of the proneural gene Cash4 in the stem zone, which in turn induces the Notch ligand Delta1. 20,25 In addition, consistent with its proliferative activity, FGF signalling maintains Cyclin D2 expression in the caudal neural plate. 26 How FGF signaling inhibits the expression of genes involved in DV patterning of the neural tube is not clear.…”

“…In this region, known as the caudal stem cell zone, neural progenitors are maintained in a proliferative, undifferentiated state, by FGF signalling, mainly FGF8 ligand emanating from the surrounding presomitic mesoderm. [19][20][21] Moreover, within the caudal stem zone, FGF signalling appears to inhibit the expression of several factors that are later induced in neural progenitors. These include a number of the key DV patterning genes such as Pax6, Irx3 and Dbx1/2.…”

Localised axial progenitor cell populations in the avian tail bud are not committed to a posterior Hox identity

“…Closer morphological inspection of the posterior tail bud identifies the dorsal epithelium of the neural tube (medullary cord), which runs further posteriorly than does the CNH in both mouse and chick, eventually becoming indistinct from the TBM. This region comprises the remnant of the stem zone, which contains neural progenitor cells for the spinal cord of the tail bud (Catala et al, 1995;Delfino-Machín et al, 2005;Diez del Coral et al, 2004). A striking difference between the chicken and the mouse is the lack of laminin staining of the posterior surface ectoderm of the chicken tail bud at these stages (arrowheads, Fig.…”

Opposing Biological Functions of Retinoic Acid in Normal Embryonic Development

“…Previous studies have shown that the epiblast cells around the embryonic primitive streak have a dual fate, either penetrate beneath the CNP to create paraxial mesoderm (somite) forming ribs, vertebrae and muscle or reside in CNP to become neural precursor cell. It has been shown that FGF signaling has a major role in this decision and RA secreting from embryonic somite converts the neural precursor cells to the differentiated neurons through attenuating the FGF signaling [13][14][15] .…”