A new role of hindbrain boundaries as pools of neural stem/progenitor cells regulated by Sox2

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.

Yap/Taz-TEAD ACTIVITY LINKS MECHANICAL CUES TO CELL PROGENITOR BEHAVIOR DURING HINDBRAIN SEGMENTATION

“…Why do hindbrain boundary cells display different mechanical features, cell fate and functional properties than their neighbors? Boundary cells coordinately unfold distinct functional properties over the entire program of hindbrain morphogenesis, first as an elastic mesh to prevent cell intermingling (Calzolari et al, 2014), then as a node for signaling pathways (for review see Terriente & Pujades, 2015), and finally, they provide proliferating progenitors and differentiating neurons to the hindbrain (Figure 4; Peretz et al, 2016). It is appealing to speculate that hindbrain boundaries undergo a tinkering strategy (Jacob, 1977), and the biological structure is "co-opted" to provide different solutions to the current challenges.…”

“…During neurogenesis, hindbrain boundaries constitute a node for signaling pathways instructing the differentiation and organization of neurons in the neighboring rhombomeres (Cheng et al, 2004;Riley et al, 2004;Cooke et al, 2005;Terriente et al, 2012). Moreover, boundary cells provide proliferating progenitors and differentiating neurons to the hindbrain (Peretz et al, 2016). However, how boundary cells make these functional transitions is largely unknown.…”

Cellular organization and boundary formation in craniofacial development

“…Specialized boundary cells at inter‐rhombomere borders are critical for patterning of the hindbrain (Guthrie & Lumsden, ; Heyman, Faissner, & Lumsden, ; Xu et al, ). In chick, it has been demonstrated that border cells include a population of Sox2‐expressing neural progenitor cells that give rise to neurons of both adjacent rhombomeres (Peretz et al, ). In zebrafish, these boundary cells express the chemorepellants Sema3fb and Sema3gb, which are critical for maintaining the positioning of Nrp2a‐expressing neuronal populations within the rhombomere (Terriente, Gerety, Watanabe‐Asaka, Gonzalez‐Quevedo, & Wilkinson, ).…”

The role of PHOX2B‐derived astrocytes in chemosensory control of breathing and sleep homeostasis

“…Ventricular zone cells are SOX2 ‐positive multipotent stem/progenitor cells (Peretz et al . ), and therefore PHOX2B expression in the hindbrain ventricular zone raises the possibility that PHOX2B ‐biased neural stem cells are also capable of forming glia. The existence of chemosensitive astrocytes (Gourine et al .…”