A neural progenitor mitotic wave is required for asynchronous axon outgrowth and morphology
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Evaluation Summary:
This study investigates development of the mechanosensory organ on Drosophila notum using various genetic techniques. They combine live imaging, mathematical modelling, genetics and behavioural analysis to show that in the peripheral nervous system of Drosophila, entry of progenitor cells into mitosis is spatially and temporally controlled. This, the authors suggest ensures proper targeting of sensory neurons within the ventral nerve cord. The study will be of broad interest to those who work on developmental processes, and particularly to those interested in sense organ development.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)
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Abstract
Spatiotemporal mechanisms generating neural diversity are fundamental for understanding neural processes. Here, we investigated how neural diversity arises from neurons coming from identical progenitors. In the dorsal thorax of Drosophila , rows of mechanosensory organs originate from the division of sensory organ progenitor (SOPs). We show that in each row of the notum, an anteromedial located central SOP divides first, then neighbouring SOPs divide, and so on. This centrifugal wave of mitoses depends on cell-cell inhibitory interactions mediated by SOP cytoplasmic protrusions and Scabrous, a secreted protein interacting with the Delta/Notch complex. Furthermore, when this mitotic wave was reduced, axonal growth was more synchronous, axonal terminals had a complex branching pattern and fly behaviour was impaired. We show that the temporal order of progenitor divisions influences the birth order of sensory neurons, axon branching and impact on grooming behaviour. These data support the idea that developmental timing controls axon wiring neural diversity.
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Evaluation Summary:
This study investigates development of the mechanosensory organ on Drosophila notum using various genetic techniques. They combine live imaging, mathematical modelling, genetics and behavioural analysis to show that in the peripheral nervous system of Drosophila, entry of progenitor cells into mitosis is spatially and temporally controlled. This, the authors suggest ensures proper targeting of sensory neurons within the ventral nerve cord. The study will be of broad interest to those who work on developmental processes, and particularly to those interested in sense organ development.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name …
Evaluation Summary:
This study investigates development of the mechanosensory organ on Drosophila notum using various genetic techniques. They combine live imaging, mathematical modelling, genetics and behavioural analysis to show that in the peripheral nervous system of Drosophila, entry of progenitor cells into mitosis is spatially and temporally controlled. This, the authors suggest ensures proper targeting of sensory neurons within the ventral nerve cord. The study will be of broad interest to those who work on developmental processes, and particularly to those interested in sense organ development.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Using live imaging approaches, the authors first document that developing sense organ precursors (SOPs) - which develop in rows on the fly thorax - initiate divisions in a wave that starts in the middle and proceeds both anteriorly and posteriorly. They also observe that prior to mitosis, SOPs send out extensive filopodial extensions through which they contact neighbouring SOPs. These extensions are withdrawn during mitosis. Based on these observations, the authors develop a mathematical model that invokes an inhibitor and an activator of mitosis: Mitosis only occurs when the concentration of the activator reaches a certain threshold; prior to mitosis, the inhibitor keeps the activator below threshold through cell-cell interactions.
The authors test their model in two ways. First they abrogate cell …
Reviewer #1 (Public Review):
Using live imaging approaches, the authors first document that developing sense organ precursors (SOPs) - which develop in rows on the fly thorax - initiate divisions in a wave that starts in the middle and proceeds both anteriorly and posteriorly. They also observe that prior to mitosis, SOPs send out extensive filopodial extensions through which they contact neighbouring SOPs. These extensions are withdrawn during mitosis. Based on these observations, the authors develop a mathematical model that invokes an inhibitor and an activator of mitosis: Mitosis only occurs when the concentration of the activator reaches a certain threshold; prior to mitosis, the inhibitor keeps the activator below threshold through cell-cell interactions.
The authors test their model in two ways. First they abrogate cell extensions through mis-expression of dominant negative Rac and observe that the wave of divisions becomes more synchronous, thus demonstrating that cell-cell interactions are necessary for the wave. They next test the molecular mechanism of inhibition. They focus on Sca and D (part of the Notch pathway). A null mutant for sca, as well as double heterozygotes for sca and D also result in synchrony of divisions, suggesting that Sca (through D) is the inhibitor. They observe that Sca is expressed in the filopodial extensions, and that the extensions themselves are not affected in sca mutants. Finally, the authors investigate the implications of wave/synchronous divisions for axon targeting and resultant behaviour and observe that both are affected when the SOP divisions occur simultaneously.
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Reviewer #2 (Public Review):
In this manuscript, Lacoste et al. closely examined division timing of sensory organ progenitors (SOP) in Drosophila notum, and found a wave-like propagation of mitoses within each proneural row. They modeled this mitotic wave on the assumption of two hypothetical components, pro-mitotic factor that is produced cell-intrinsically at a constant rate and anti-mitotic signal that is transmitted by the neighboring pre-mitotic SOPs in a cell contact-dependent manner. They showed that the mitotic wave becomes more synchronous when the dominant-negative form Rac1 is expressed in SOPs or when the expression of scabrous implicated in Notch signaling is down-regulated, possibly by reducing the anti-mitotic signal between SOPs. The authors furthermore showed that axon branching patterns from the sensory organ and the …
Reviewer #2 (Public Review):
In this manuscript, Lacoste et al. closely examined division timing of sensory organ progenitors (SOP) in Drosophila notum, and found a wave-like propagation of mitoses within each proneural row. They modeled this mitotic wave on the assumption of two hypothetical components, pro-mitotic factor that is produced cell-intrinsically at a constant rate and anti-mitotic signal that is transmitted by the neighboring pre-mitotic SOPs in a cell contact-dependent manner. They showed that the mitotic wave becomes more synchronous when the dominant-negative form Rac1 is expressed in SOPs or when the expression of scabrous implicated in Notch signaling is down-regulated, possibly by reducing the anti-mitotic signal between SOPs. The authors furthermore showed that axon branching patterns from the sensory organ and the organ-mediated behavior in flies are impaired in the scabrous mutant, and hypothesize that these defects originate from changes in differentiation timing of the sensory organ caused by the flattened SOP mitotic wave.
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Reviewer #3 (Public Review):
In this manuscript, Lacoste et al., investigate how neuronal diversity arises during the development of the peripheral nervous system. The authors use the Drosophila sensory organ precursors (SOPs), a pool of progenitor cells that give rise to the mechanosensory bristles of the adult fly to explore the spatiotemporal aspects of this process. By combining live imaging, mathematical modelling, genetics and behavioural assays the authors show that the timing of sensory neuron differentiation is controlled by spatially and temporally controlled entry of SOPs into mitosis. This timing is important for axonogenesis and proper spatial arborization, and its perturbation by interfering with the fibrinogen-like protein Scabrous leads to a defective response to tactile bristle stimulation. Overall, this paper provides …
Reviewer #3 (Public Review):
In this manuscript, Lacoste et al., investigate how neuronal diversity arises during the development of the peripheral nervous system. The authors use the Drosophila sensory organ precursors (SOPs), a pool of progenitor cells that give rise to the mechanosensory bristles of the adult fly to explore the spatiotemporal aspects of this process. By combining live imaging, mathematical modelling, genetics and behavioural assays the authors show that the timing of sensory neuron differentiation is controlled by spatially and temporally controlled entry of SOPs into mitosis. This timing is important for axonogenesis and proper spatial arborization, and its perturbation by interfering with the fibrinogen-like protein Scabrous leads to a defective response to tactile bristle stimulation. Overall, this paper provides interesting new insights into how spatial and temporal aspects of neuronal development can shape connectivity.
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