Abstract
BackgroundCompartment boundaries are an essential developmental mechanism throughout evolution, designated to act as organizing centers and to regulate and localize differently fated cells. The hindbrain serves as a fascinating example for this phenomenon as its early development is devoted to the formation of repetitive rhombomeres and their well-defined boundaries in all vertebrates. Yet, the actual role of hindbrain boundaries remains unresolved, especially in amniotes.ResultsHere, we report that hindbrain boundaries in the chick embryo consist of a subset of cells expressing the key neural stem cell (NSC) gene Sox2. These cells co-express other neural progenitor markers such as Transitin (the avian Nestin), GFAP, Pax6 and chondroitin sulfate proteoglycan. The majority of the Sox2+ cells that reside within the boundary core are slow-dividing, whereas nearer to and within rhombomeres Sox2+ cells are largely proliferating. In vivo analyses and cell tracing experiments revealed the contribution of boundary Sox2+ cells to neurons in a ventricular-to-mantle manner within the boundaries, as well as their lateral contribution to proliferating Sox2+ cells in rhombomeres. The generation of boundary-derived neurospheres from hindbrain cultures confirmed the typical NSC behavior of boundary cells as a multipotent and self-renewing Sox2+ cell population. Inhibition of Sox2 in boundaries led to enhanced and aberrant neural differentiation together with inhibition in cell-proliferation, whereas Sox2 mis-expression attenuated neurogenesis, confirming its significant function in hindbrain neuronal organization.ConclusionsData obtained in this study deciphers a novel role of hindbrain boundaries as repetitive pools of neural stem/progenitor cells, which provide proliferating progenitors and differentiating neurons in a Sox2-dependent regulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0277-y) contains supplementary material, which is available to authorized users.
Highlights
Compartment boundaries are an essential developmental mechanism throughout evolution, designated to act as organizing centers and to regulate and localize differently fated cells
The facts that boundary-specific genes are shared by all boundaries and that rhombomere markers (i.e., Hoxb1, Krox20) are lost from boundary cells over time [15] led us to hypothesize that boundaries may differ from rhombomeres in their neural differentiation state
At st.16–17, SRY-related HMG-box 2 gene (Sox2)+ cells are still present in rhombomeres, yet enhanced Sox2 expression can be detected in hindbrain boundaries (HBs) (Fig. 1Ab,e; n = 10)
Summary
Compartment boundaries are an essential developmental mechanism throughout evolution, designated to act as organizing centers and to regulate and localize differently fated cells. Groups of cells with similar fates and functions are often separated from other cells by the formation of sharp boundaries. Such boundaries are fundamental during the development of the central nervous system (CNS), where they act as organizing centers to pattern the tissue and localize differently-fated cells via the secretion of signaling molecules [1, 2]. The MHB acts as an organizing center that expresses signaling factors, such as Wnts and FGF8, and regulates distinct gene expression patterns and neuronal fates of midbrain and anterior hindbrain cells [20,21,22,23,24]. Studies in zebrafish and mice have highlighted the role of the Notch effector group of Hes genes, which are expressed in MHB cells, to repress them from undergoing differentiation while promoting neurogenesis in the adjacent domains [28,29,30,31,32,33]
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