Mitotic spindle orientation distinguishes stem cell and terminal modes of neuron production in the early spinal cord

Abstract

*Despite great insight into the molecular mechanisms that specify neuronal cell type in the spinal cord, cell behaviour underlying neuron production in this tissue is largely unknown. In other neuroepithelia, divisions with a perpendicular cleavage plane at the apical surface generate symmetrical cell fates, whereas a parallel cleavage plane generates asymmetric daughters, a neuron and a progenitor in a stem cell mode, and has been linked to the acquisition of neuron-generating ability. Using a novel long-term imaging assay, we have monitored single cells in chick spinal cord as they transit mitosis and daughter cells become neurons or divide again. We reveal new morphologies accompanying neuron birth and show that neurons are generated concurrently by asymmetric and terminal symmetric divisions. Strikingly, divisions that generate two progenitors or a progenitor and a neuron both exhibit a wide range of cleavage plane orientations and only divisions that produce two neurons have an exclusively perpendicular orientation. Neuron-generating progenitors are also distinguished by lengthening cell cycle times, a finding supported by cell cycle acceleration on exposure to fibroblast growth factor (FGF), an inhibitor of neuronal differentiation. This study provides a novel, dynamic view of spinal cord neurogenesis and supports a model in which cleavage plane orientation/mitotic spindle position does not assign neurongenerating ability, but functions subsequent to this step to distinguish stem cell and terminal modes of neuron production.

Cerebrospinal fluid-derived Semaphorin3B orients neuroepithelial cell divisions in the apicobasal axis

“…Similarly, division orientation could differ between progenitors giving rise to two progenitors fated to undergo division mode similar or different to the mother type. Progenitors giving rise to two neurons and to two progenitors could also divide with slightly different angles 12 .…”

“…However, this binary classification may mask a diversity of mitotic spindle orientation proceedings reflecting the concomitance of various neural progenitor populations. Depending on the progenitor types, the divisions give rise to either two neurons, or one progenitor and one neuron, or to two progenitors, the daughter progenitors reproducing or not mother cell division mode 11,12 . Although this great diversity of dividing cells is not yet distinguishable by molecular markers, specific controls might exist for each of these co-existing progenitor divisions, which have not been investigated yet.…”

Mapping differentiation kinetics in the mouse retina reveals an extensive period of cell cycle protein expression in post‐mitotic newborn neurons

“…Increase in the length of G1 has been associated with promoting cell cycle exit and differentiation in the CNS; however, whether the cell cycle kinetics are the cause or consequence of neuronal progenitor fate decisions is still debated (Gotz and Huttner, 2005;Dehay and Kennedy, 2007;Wilcock et al, 2007;Lange and Calegari, 2010;Arai et al, 2011). Whether G2/ M length also affects progenitor fate is also of interest.…”

Diversity in the molecular and cellular strategies of epithelium-to-mesenchyme transitions: Insights from the neural crest

“…Both tissues are composed of cuboidal cells expressing cytokeratins symmetrical, resulting in two identical daughter cells which soon re-establish contact with the basement membrane. 47 Albeit neural epithelial cells are fully polarized, 48 they do not exhibit the whole range of cellular and molecular features of flat, cuboidal epithelia. In particular, they lack tight junctions and express vimentin intead of cytokeratins.…”