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There’s a time and a place for differentiation


Researchers have uncovered protrusive activity of newborn neurons that, by delivering transient lateral inhibition over an extended range, organises unexpectedly long-distance spatiotemporal patterning of differentiation.

Differentiating spinal neurons were shown to extend two long protrusions several cell diameters in length along the basal surface of the spinal cord before axogenesis. These protrusions that last a few hours, mediate transient long-range lateral inhibition.

The CDN’s Rachel Moore, Rebecca McIntosh and Jon Clarke collaborated with colleagues in Geneva and at UCL on the new paper, published in Developmental Cell. They found novel cellular behaviour for vertebrate neurons that regulates the spatiotemporal dynamics of neuronal differentiation along the spinal cord, using in vivo imaging in zebrafish and theoretical models.

The researchers found that differentiating neurons and non-apical progenitors transiently develop two long, basal protrusions prior to apical detachment and axiogenesis. These protrusions express the Delta protein at high levels and activate Notch signalling in surrounding cells at a distance from the neuronal cell body. Their findings uncover a mechanism for the long-distance spacing pattern of spinal neuron differentiation that could not be explained by conventional short range lateral inhibition.

Experimental manipulation of basal protrusions in vivo were supported by a mathematical model of cells with and without signalling basal protrusions. Previous work in the fly peripheral nervous system described the role of basal protrusions in mediating lateral inhibition at a distance to regulate the position of sensory neuron differentiation. This study has shown, for the first time, that a similar cell-protrusion-mediated mechanism operates in the spinal cord of a vertebrate.

The authors of this study propose that the biological function of regulating neuronal differentiation in a spatiotemporal manner may be advantageous for neuronal circuit formation if the initial connections are made between a minimal number of spatially distributed neurons. Differentiating neurons can then be added later to a functioning circuit to consolidate, extend or modify the circuit function. This advantage could be especially important for zebrafish and amphibian embryos that develop externally and need to quickly build a functional motor circuit to survive, but may be applicable to other more complex systems and species.