Abstract
SummaryDuring early spinal cord development, neurons of particular subtypes differentiate with a sparse periodic pattern while later neurons differentiate in the intervening space to eventually produce continuous columns of similar neurons. The mechanisms that regulate this spatiotemporal pattern are unknown. In vivo imaging in zebrafish reveals that differentiating spinal neurons transiently extend two long protrusions along the basal surface of the spinal cord before axon initiation. These protrusions express Delta protein, consistent with the hypothesis they influence Notch signaling at a distance of several cell diameters. Experimental reduction of Laminin expression leads to smaller protrusions and shorter distances between differentiating neurons. The experimental data and a theoretical model support the proposal that neuronal differentiation pattern is regulated by transient basal protrusions that deliver temporally controlled lateral inhibition mediated at a distance. This work uncovers a stereotyped protrusive activity of newborn neurons that organize long-distance spatiotemporal patterning of differentiation.
Highlights
During the early stages of vertebrate neurogenesis, neurons of particular subtypes initially differentiate along the spinal cord with a sparse periodic pattern but eventually produce more continuous columns of similar neurons (Figure 1A; Dale et al, 1987; Roberts et al, 1987; Higashijima et al, 2004a, 2004b; Kimura et al, 2006; Batista et al, 2008; England et al, 2011)
DeltaNotch-mediated lateral inhibition is a regulator of vertebrate neurogenesis (Chitnis et al, 1995; Henrique et al, 1997; Appel et al, 2001; Okigawa et al, 2014), but this conventionally operates in a juxtacrine fashion between Delta-expressing cells and their immediate neighbors and cannot explain the spatial and temporal pattern of neuronal differentiation along the embryo spinal cord
To determine whether cellular protrusions could play a role in the patterning of spinal neuronal differentiation, we addressed these issues in the zebrafish embryo spinal cord
Summary
During the early stages of vertebrate neurogenesis, neurons of particular subtypes initially differentiate along the spinal cord with a sparse periodic pattern but eventually produce more continuous columns of similar neurons (Figure 1A; Dale et al, 1987; Roberts et al, 1987; Higashijima et al, 2004a, 2004b; Kimura et al, 2006; Batista et al, 2008; England et al, 2011). DeltaNotch-mediated lateral inhibition is a regulator of vertebrate neurogenesis (Chitnis et al, 1995; Henrique et al, 1997; Appel et al., 2001; Okigawa et al, 2014), but this conventionally operates in a juxtacrine fashion between Delta-expressing cells and their immediate neighbors and cannot explain the spatial and temporal pattern of neuronal differentiation along the embryo spinal cord. Dynamic cellular protrusions from the basal surface of sensory organ precursor (SOP) cells have been proposed to mediate long-distance lateral inhibition to regulate the sparse distribution of mechanosensory bristles in the fly notum and wing disk (De Joussineau et al, 2003; Cohen et al, 2010; Hadjivasiliou et al, 2016; Hunter et al, 2016, 2019). Dynamic protrusive activity on the surface of recently born spinal neurons can be observed in slice cultures of chick embryo spinal cord (Das and Storey, 2014)
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