Abstract
A complete account of the whole developmental process of neurogenesis involves understanding a number of complex underlying molecular processes. Among them, those that govern the crucial transition from proliferative (self-replicating) to neurogenic neural progenitor (NP) cells remain largely unknown. Due to its sequential rostro-caudal gradients of proliferation and neurogenesis, the prospective spinal cord of the chick embryo is a good experimental system to study this issue. We report that the NOTCH ligand DELTA-1 is expressed in scattered cycling NP cells in the prospective chick spinal cord preceding the onset of neurogenesis. These Delta-1-expressing progenitors are placed in between the proliferating caudal neural plate (stem zone) and the rostral neurogenic zone (NZ) where neurons are born. Thus, these Delta-1-expressing progenitors define a proliferation to neurogenesis transition zone (PNTZ). Gain and loss of function experiments carried by electroporation demonstrate that the expression of Delta-1 in individual progenitors of the PNTZ is necessary and sufficient to induce neuronal generation. The activation of NOTCH signalling by DELTA-1 in the adjacent progenitors inhibits neurogenesis and is required to maintain proliferation. However, rather than inducing cell cycle exit and neuronal differentiation by a typical lateral inhibition mechanism as in the NZ, DELTA-1/NOTCH signalling functions in a distinct manner in the PNTZ. Thus, the inhibition of NOTCH signalling arrests proliferation but it is not sufficient to elicit neuronal differentiation. Moreover, after the expression of Delta-1 PNTZ NP continue cycling and induce the expression of Tis21, a gene that is upregulated in neurogenic progenitors, before generating neurons. Together, these experiments unravel a novel function of DELTA–NOTCH signalling that regulates the transition from proliferation to neurogenesis in NP cells. We hypothesize that this novel function is evolutionary conserved.
Highlights
One of the greatest challenges in the field of neural development is to elucidate how developmental signals are integrated to generate the wide cellular diversity of the brain
We found numerous scattered Delta-1-expressing cells in the caudal region where neurons are practically absent. It appears that Delta-1 expression in single cells of the caudal spinal cord precedes the onset of neurogenesis
In the caudal region, they were found in all apico-basal positions of the neuroepithelium (Fig. 1E), suggesting that Delta-1 may be expressed by neural progenitor (NP) cells of the caudal spinal cord
Summary
One of the greatest challenges in the field of neural development is to elucidate how developmental signals are integrated to generate the wide cellular diversity of the brain. The whole developmental process of neurogenesis comprises several cellular steps including the switch to neurogenic NP cells, the cell cycle exit after division of at least one of the daughter cells, and its differentiation into a neuron or glial cell [7,8,9,10]. Numerous molecular mechanisms involved in the regulation of the asymmetric division of NP [11,12], cell cycle exit of neural cells [13,14] and neuronal differentiation [15] have been extensively studied. The genes and molecular processes that govern the switch from proliferative to neurogenic NP cells remain mostly unknown and, little is known of how these sequential steps are coordinated
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