Synergistic Activity of Floor-Plate- and Ventricular-Zone-Derived Netrin-1 in Spinal Cord Commissural Axon Guidance

Moreno-Bravo, Juan Antonio; Puiggros, Sergi Roig; Mehlen, Patrick; Chédotal, Alain

doi:10.1016/j.neuron.2018.12.024

Cited by 52 publications

(51 citation statements)

References 37 publications

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“…Shh::cre;Ntn1 lox/lox mice is a viable mouse model, in which Ntn1 depletion is restricted to the floor plate in the regions of the CNS located caudal to the midbrain/hindbrain boundary. Interestingly, midline crossing of spinal cord and hindbrain commissural axons is mostly preserved in this model [11][12][13][14] . Yet, development of the corticospinal axons, which occurs over a protracted period, has not been investigated in these mice.…”

Section: Introductionmentioning

confidence: 73%

“…This unveils a distinct and unique guidance mechanism for corticospinal axons, since FP-Netrin-1 was proven to be dispensable or mostly dispensable for midline crossing of hindbrain commissural axons and spinal commissural axons respectively. Guidance of these ventral commissural axons, which occurs during early embryonic stages, relies mainly on another source of Netrin-1, produced by the progenitor cells of the ventricular zone [11][12][13][14] . Interestingly, at the time when corticospinal axons cross the CNS midline (around birth), these progenitor cells are virtually absent 19 .…”

Section: Discussionmentioning

confidence: 99%

“…In Shh::cre;Ntn1 lox/lox mice, disruption of the CST decussation results in abnormal but functional ipsilateral projections. Previous characterization of Shh::cre;Ntn1 lox/lox mice revealed that guidance of commissural axons in the spinal cord was mostly preserved [11][12][13][14] . In Shh::cre;Ntn1 lox/lox mice, we found no alteration of Ntn1 expression in the forebrain ( Supplementary Fig.…”

Section: Abnormalities Of Motor Tracts Are Restricted To the Cst In Smentioning

confidence: 99%

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Loss of floor plate Netrin-1 impairs midline crossing of corticospinal axons and leads to mirror movements

Pourchet

Morel

Welniarz

et al. 2020

Preprint

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In human, execution of unimanual movements requires lateralized activation of the primary motor cortex, which then transmits the motor command to the contralateral hand through the crossed corticospinal tract (CST). Mutations in NETRIN-1 alter motor control lateralization, leading to congenital mirror movements. To address the role of midline Netrin-1 on CST development and subsequent motor control, we analyzed the morphological and functional consequences of floor-plate Netrin-1 depletion in conditional knock-out mice (Shh::cre;Ntn1 lox/lox mice). Here, we show that depletion of floor plate Netrin-1 critically disrupts midline crossing of the CST, whereas the other commissural systems are mostly preserved. The CST defect results in abnormal but functional ipsilateral projections, and is associated with abnormal symmetric movements. Therefore, our study reveals a new role for Netrin-1 in CST development. It also describes a unique mouse model recapitulating characteristics of human congenital mirror movements, through abnormal CST decussation.

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Section: Introductionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Abnormalities Of Motor Tracts Are Restricted To the Cst In Smentioning

confidence: 99%

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Loss of floor plate Netrin-1 impairs midline crossing of corticospinal axons and leads to mirror movements

Pourchet

Morel

Welniarz

et al. 2020

Preprint

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“…Testing such a model is not straightforward as one would not expect axons to become completely lost but instead to be slightly slower or make more mistakes en route. Identifying these types of subtle guidance defects will require analysis of individual axon trajectories and more careful quantification, similar to how a role for floor plate-derived Netrin-1 was demonstrated 8,9 . It is also possible that the glia themselves provide additional synergizing cues that directly impact neurite outgrowth behavior.…”

Section: Discussionmentioning

confidence: 99%

Early neuronal processes interact with glia to establish a scaffold for orderly innervation of the cochlea

Druckenbrod

Hale

Olukoya

et al. 2019

Preprint

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Authors' contributions: This study was conceived of and designed by NRD and LVG. NRD, EBH, OOO, and WES performed experiments and analyzed results. LVG analyzed results and wrote the manuscript. Summary:Although the basic principles of axon guidance are well established, it remains unclear how axons navigate with high fidelity through the complex cellular terrains that are encountered in vivo. To learn more about the cellular strategies underlying axon guidance in vivo, we analyzed the developing cochlea, where spiral ganglion neurons extend processes through a heterogeneous cellular environment to form tonotopically ordered connections with hair cells. Here, we show that the earliest processes are closely associated with a population of glia that grow ahead of them. By analyzing single cell morphology and imaging the real time behavior of neuronal processes and glia in embryonic cochleae, we show that spiral ganglion neurons employ different mechanisms depending on their position in the ganglion. Additionally, the pattern of outgrowth varied locally, with evidence for both glia-guided growth and fasciculation along a neuronal scaffold. These findings suggest a tiered mechanism for reliable axon guidance. Introduction:Neuroscientists have long puzzled how neurons make the connections needed for proper circuit function, with early mechanical explanations by Weiss 1 (1941) eventually set aside in favor of Sperry's chemoaffinity hypothesis 2 . With the discovery of axon guidance molecules, the field coalesced around the idea that axons are guided towards their targets by a combination of attractive and repulsive cues that act at short or long range, with direction specified by targetderived gradients 3 . However, mathematical modeling studies suggest that chemoattractive gradients are not solely responsible for the remarkable precision of guidance events in vivo, where axons grow through complex and changing environments 4 . Although synergy among cues may improve fidelity, other cellular mechanisms likely contribute, such as fasciculation with pioneers and avoidance of repellant boundaries 5 . For instance, in the spinal cord, commissural axons grow along a permissive substrate of Netrin-1 in the subpial region before turning towards an instructive gradient of Netrin-1 and other cues emanating from the floor plate 6-9 , underscoring the idea that axons rely on different mechanisms as they move through distinct cellular landscapes.The cochlea presents a distinct landscape for axon growth compared to the spinal cord, with neural processes organized into a spatial stereotyped pattern within a highly heterogeneous cellular environment. The cochlea is comprised of three fluid-filled ducts: scala vestibuli, scala media, and scala tympani (Fig. 1a). The auditory sensory epithelium, the organ of Corti, sits on the floor of scala media and vibrates in response to wavelengths of sound, thereby activating sensory hair cells. Information is transmitted to the central nervous system by the spiral ganglion neurons (SGNs), whose ...

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“…More specifically, netrin1 from the floorplate of the developing hindbrain is dispensable for midline crossing (Dominici et al, 2017;Yamauchi et al, 2017), which is mostly regulated by netrin1 distributed along the axon path and derived from ventricular zone progenitor progenitors instead. In the spinal cord, both netrin from both sources act synergistically as both short-and long-range cues to guide midline crossing (Dominici et al, 2017;Moreno-Bravo et al, 2019;Varadarajan et al, 2017;Wu et al, 2019). Furthermore, a role for UNC-6/netrin in C. elegans is instructive for neuronal polarization and defines the site of axonogensis (Adler et al, 2006).…”

Section: Ddns Upregulate Extracellular Matrix Proteins and The Axon Gmentioning

confidence: 99%

Neuron subtype-specific effector gene expression in the Motor Ganglion of Ciona

Gibboney

Kim

Johnson

et al. 2019

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The central nervous system of the Ciona larva contains only 177 neurons. The precise regulation of neuron subtype-specific morphogenesis and differentiation observed in during the formation of this minimal connectome offers a unique opportunity to dissect gene regulatory networks underlying chordate neurodevelopment. Here we compare the transcriptomes of two very distinct neuron types in the hindbrain/spinal cord homolog of Ciona, the Motor Ganglion (MG): the Descending decussating neuron (ddN, proposed homolog of Mauthner Cells in vertebrates) and the MG Interneuron 2 (MGIN2). Both types are invariantly represented by a single bilaterally symmetric left/right pair of cells in every larva. Supernumerary ddNs and MGIN2s were generated in synchronized embryos and isolated by fluorescence-activated cell sorting for transcriptome profiling. Differential gene expression analysis revealed ddN-and MGIN2specific enrichment of a wide range of genes, including many encoding potential "effectors" of subtype-specific morphological and functional traits. More specifically, we identified the upregulation of centrosome-associated, microtubule-stabilizing/bundling proteins and extracellular matrix proteins and axon guidance cues as part of a single intrinsic regulatory program that might underlie the unique polarization of the ddNs, the only descending MG neurons that cross the midline.

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Synergistic Activity of Floor-Plate- and Ventricular-Zone-Derived Netrin-1 in Spinal Cord Commissural Axon Guidance

Cited by 52 publications

References 37 publications

Loss of floor plate Netrin-1 impairs midline crossing of corticospinal axons and leads to mirror movements

Loss of floor plate Netrin-1 impairs midline crossing of corticospinal axons and leads to mirror movements

Early neuronal processes interact with glia to establish a scaffold for orderly innervation of the cochlea

Neuron subtype-specific effector gene expression in the Motor Ganglion of Ciona

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