Netrin‐1 is required for efficient neural tube closure

Kee, Nigel; Wilson, Nicole H.; Key, Brian; Cooper, Helen

doi:10.1002/dneu.22051

Cited by 10 publications

(13 citation statements)

References 43 publications

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“…5, 6C), suggesting that the opposing actions of RGMa and Netrin-1 ensure migrating interneurons are restricted to the correct migratory pathway. An interplay between RGMa- and Netrin-1-mediated Neo activity has also been observed during Xenopus neural tube formation [43], [44]. In this developmental system RGMa and Netrin-1 were expressed in complementary gradients across the neural plate and loss of either ligand or Neo produced delayed neural tube closure.…”

Section: Discussionmentioning

confidence: 82%

RGMa Regulates Cortical Interneuron Migration and Differentiation

et al. 2013

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The etiology of neuropsychiatric disorders, including schizophrenia and autism, has been linked to a failure to establish the intricate neural network comprising excitatory pyramidal and inhibitory interneurons during neocortex development. A large proportion of cortical inhibitory interneurons originate in the medial ganglionic eminence (MGE) of the ventral telencephalon and then migrate through the ventral subventricular zone, across the corticostriatal junction, into the embryonic cortex. Successful navigation of newborn interneurons through the complex environment of the ventral telencephalon is governed by spatiotemporally restricted deployment of both chemorepulsive and chemoattractive guidance cues which work in concert to create a migratory corridor. Despite the expanding list of interneuron guidance cues, cues responsible for preventing interneurons from re-entering the ventricular zone of the ganglionic eminences have not been well characterized. Here we provide evidence that the chemorepulsive axon guidance cue, RGMa (Repulsive Guidance Molecule a), may fulfill this function. The ventricular zone restricted expression of RGMa in the ganglionic eminences and the presence of its receptor, Neogenin, in the ventricular zone and on newborn and maturing MGE-derived interneurons implicates RGMa-Neogenin interactions in interneuron differentiation and migration. Using an in vitro approach, we show that RGMa promotes interneuron differentiation by potentiating neurite outgrowth. In addition, using in vitro explant and migration assays, we provide evidence that RGMa is a repulsive guidance cue for newborn interneurons migrating out of the ganglionic eminence ventricular zone. Intriguingly, the alternative Neogenin ligand, Netrin-1, had no effect on migration. However, we observed complete abrogation of RGMa-induced chemorepulsion when newborn interneurons were simultaneously exposed to RGMa and Netrin-1 gradients, suggesting a novel mechanism for the tight regulation of RGMa-guided interneuron migration. We propose that during peak neurogenesis, repulsive RGMa-Neogenin interactions drive interneurons into the migratory corridor and prevent re-entry into the ventricular zone of the ganglionic eminences.

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Section: Discussionmentioning

confidence: 82%

RGMa Regulates Cortical Interneuron Migration and Differentiation

et al. 2013

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“…Neogenin mediates axon guidance in the embryonic nervous system [24][25][26][27][28][29][30]. It is also important for neural tube and endochondral bone formation, digit patterning, and muscle differentiation [31][32][33][34][35]. In the context of axon guidance, Neogenin promotes chemoattraction in response to the secreted guidance cue, Netrin-1, and chemorepulsion in response to RGMa (repulsive guidance molecule a) [29,30].…”

Section: Introductionmentioning

confidence: 99%

The Netrin/RGM Receptor, Neogenin, Controls Adult Neurogenesis by Promoting Neuroblast Migration and Cell Cycle Exit

et al. 2015

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A comprehensive understanding of adult neurogenesis is essential for the development of effective strategies to enhance endogenous neurogenesis in the damaged brain. Olfactory interneurons arise throughout life from stem cells residing in the subventricular zone of the lateral ventricle. Neural precursors then migrate along the rostral migratory stream (RMS) to the olfactory bulb. To ensure a continuous supply of adult-born interneurons, precursor proliferation, migration, and differentiation must be tightly coordinated. Here, we show that the netrin/repulsive guidance molecule receptor, Neogenin, is a key regulator of adult neurogenesis. Neogenin loss-of-function (Neo gt/gt ) mice exhibit a specific reduction in adult-born calretinin interneurons in the olfactory granule cell layer. In the absence of Neogenin, neuroblasts fail to migrate into the olfactory bulb and instead accumulate in the RMS. In vitro migration assays confirmed that Neogenin is required for Netrin-1-mediated neuroblast migration and chemoattraction. Unexpectedly, we also identified a novel role for Neogenin as a regulator of the neuroblast cell cycle. We observed that those neuroblasts able to reach the Neo gt/gt olfactory bulb failed to undergo terminal differentiation. Cell cycle analysis revealed an increase in the number of S-phase neuroblasts within the Neo gt/gt RMS and a significant reduction in the number of neuroblasts exiting the cell cycle, providing an explanation for the loss of mature calretinin interneurons in the granule cell layer. Therefore, Neogenin acts to synchronize neuroblast migration and terminal differentiation through the regulation of neuroblast cell cycle kinetics within the neurogenic microenvironment of the RMS. STEM CELLS 2015;33:503-514

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“…In this case, the boundary cells remained loosely packed and unpolarized [Mawdsley et al, 2004]. Netrin is also involved in neurulation in that Xnet1 knockdown delays the neural tube apposition [Kee et al, 2013] although the formation of the neuroepithelium is normal, suggesting that Xrgma plays the primary role in polarizing these cells.…”

Section: Netrins As a Polarizing Cue In Neural And Nonneural Cell Typesmentioning

confidence: 92%

The Role of Netrins and Their Receptors in Epithelial Mesenchymal Plasticity during Development

Murray

2017

Cells Tissues Organs

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Transitions between mesenchymal and epithelial cells are underpinned by changes in motility, adhesion, and polarity. Netrins and their receptors can control each of these cellular properties, and are emerging as important regulators of epithelial mesenchymal plasticity (EMP). Netrins were first identified in the worm Caenorhabditis elegans as secreted chemoattractants/repellents that could guide migrating mesodermal cells and axonal growth cones. Orthologues were subsequently found to play conserved roles in vertebrates and in the vinegar fly Drosophila. In the years that have followed it has become clear that, in addition to chemotaxis, netrin pathways have a number of other biological roles, many of which are directly relevant to the processes of EMP. Netrins and their receptors regulate morphogenesis of epithelial branched structures in the lung, mammary gland, pancreas, and vasculature, and can also promote the loss of epithelial structure. More recently they have been shown to drive apicobasal cell polarization events in vertebrates, flies, and worms. Given these many and varied roles in regulating epithelial morphogenetic events, together with their well-established roles in cell motility, netrins are likely to remain an important future avenue for EMP research.

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Netrin‐1 is required for efficient neural tube closure

Cited by 10 publications

References 43 publications

RGMa Regulates Cortical Interneuron Migration and Differentiation

RGMa Regulates Cortical Interneuron Migration and Differentiation

The Netrin/RGM Receptor, Neogenin, Controls Adult Neurogenesis by Promoting Neuroblast Migration and Cell Cycle Exit

The Role of Netrins and Their Receptors in Epithelial Mesenchymal Plasticity during Development

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