Clonally related, Notch-differentiated spinal neurons integrate into distinct circuits
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eLife assessment
This important paper describes the connectivity of V2a/V2b sibling neurons in the zebrafish spinal cord, where one sibling receives Notch signaling (Notch-ON) and the other does not (Notch-OFF). They find that V2a and V2b siblings have different morphology, inputs, outputs, and are not synaptically connected, unlike findings in the mouse cortex. This work provides new insight into the role of lineage in specifying neuronal connectivity; the experiments are convincing and the conclusions are supported by the data presented.
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Abstract
Shared lineage has diverse effects on patterns of neuronal connectivity. In mammalian cortex, excitatory sister neurons assemble into shared microcircuits. In Drosophila , in contrast, sister neurons with different levels of Notch expression (Notch ON /Notch OFF ) develop distinct identities and diverge into separate circuits. Notch-differentiated sister neurons have been observed in vertebrate spinal cord and cerebellum, but whether they integrate into shared or distinct circuits remains unknown. Here, we evaluate how sister V2a (Notch OFF )/V2b (Notch ON ) neurons in the zebrafish integrate into spinal circuits. Using an in vivo labeling approach, we identified pairs of sister V2a/b neurons born from individual Vsx1+ progenitors and observed that they have somata in close proximity to each other and similar axonal trajectories. However, paired whole-cell electrophysiology and optogenetics revealed that sister V2a/b neurons receive input from distinct presynaptic sources, do not communicate with each other, and connect to largely distinct targets. These results resemble the divergent connectivity in Drosophila and represent the first evidence of Notch-differentiated circuit integration in a vertebrate system.
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eLife assessment
This important paper describes the connectivity of V2a/V2b sibling neurons in the zebrafish spinal cord, where one sibling receives Notch signaling (Notch-ON) and the other does not (Notch-OFF). They find that V2a and V2b siblings have different morphology, inputs, outputs, and are not synaptically connected, unlike findings in the mouse cortex. This work provides new insight into the role of lineage in specifying neuronal connectivity; the experiments are convincing and the conclusions are supported by the data presented.
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Reviewer #1 (Public Review):
This paper shows that sibling neurons in the zebrafish spinal cord have different inputs and outputs, and do not show interconnectivity - somewhat surprising considering their very similar development. The differences in sibling neuron connectivity are strongly correlated with the level of Notch signaling, suggesting that Notch signaling regulates circuit assembly.
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Reviewer #2 (Public Review):
The data presented in this manuscript provide evidence that, in the ventral spinal cord of zebrafish embryos, "sister" V2a excitatory and V2b inhibitory neurons, which arise from common vsx1+ progenitors, extend descending, ipsilateral axons that, although differing in length, remain close to one another. Because of this alignment, V2a and V2b neurons could contribute to a common microcircuit, by receiving inputs from common synaptic circuits, forming synapses on one another, or projecting to common synaptic targets. However, a series of electrophysiological and optogenetic tests exclude these possibilities and indicate that, instead, they receive inputs from distinct sources, they do not engage in synaptic signaling with one another, and they have distinct, downstream synaptic targets. This differs from the …
Reviewer #2 (Public Review):
The data presented in this manuscript provide evidence that, in the ventral spinal cord of zebrafish embryos, "sister" V2a excitatory and V2b inhibitory neurons, which arise from common vsx1+ progenitors, extend descending, ipsilateral axons that, although differing in length, remain close to one another. Because of this alignment, V2a and V2b neurons could contribute to a common microcircuit, by receiving inputs from common synaptic circuits, forming synapses on one another, or projecting to common synaptic targets. However, a series of electrophysiological and optogenetic tests exclude these possibilities and indicate that, instead, they receive inputs from distinct sources, they do not engage in synaptic signaling with one another, and they have distinct, downstream synaptic targets. This differs from the mouse cortex, in which clonally related neurons appear to preferentially form connections within a shared microcircuit.
The chief strengths of this work include the imaging data, which nicely reveal the locations and morphologies of sister V2a/b neurons, and the electrophysiological experiments, which provide compelling evidence that sister V2a/b neurons do not function within a shared microcircuit.
The study does have some limitations. First, V2a/V2b sister pairs are not obligate. Instead, about 25% of V2b neurons arise from a vsx1+ progenitor division that also produces a V2s neuron instead of a V2a neuron. To distinguish between these outcomes, the authors use the transient expression of a vsx1:EGFP reporter to label clonal pairs combined with a chx10:Red reporter to label V2a neurons. For the optogenetic experiments, however, the authors were not able to use the V2a neuron marker because they were limited by the reporters available to them. Thus, there is a possibility that some sister neurons tested were V2b/s rather than V2a/b. Second, the electrophysiological data are not paired with examinations of synaptic contacts using light or electron microscopy. Third, the circuits in which V2a and V2b neurons function are incompletely understood, and so knowledge of the synaptic inputs and downstream targets is limited.
On balance, the limitations of the study are rather minor. The manuscript is nicely written, the figures are presented clearly and logically, and the data are sufficient to support the claims and conclusions made by the authors. The results extend our knowledge of developmental strategies used to form neural circuits.
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Reviewer #3 (Public Review):
This study asks a simple question and provides a clear and convincing answer. The question is whether sister neurons derived from the same progenitor, using Notch receptor signaling as the underlying cell fate determinant, share pre- and post-synaptic partners. The answer, not in the case of V2a and V2b neurons in the fish spinal cord. Authors show that V2a and V2b neurons derived from the same progenitor are recruited to distinct spinal neural networks.
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