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Cited by 44Axon Guidance and Neuronal SignalingNeurogenesis and neuroplasticity mechanismsDevelopmental Biology and Gene Regulation

Involvement of Netrins and Their Receptors in Neuronal Migration in the Cerebral Cortex

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Yamagishi, Satoru, Bando, Yuki, Sato, Kohji·2021·Frontiers in Cell and Developmental Biology
DOI 10.3389/fcell.2020.590009PMC PMC7843923
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Abstract

In mammals, excitatory cortical neurons develop from the proliferative epithelium and progenitor cells in the ventricular zone and subventricular zone, and migrate radially to the cortical plate, whereas inhibitory GABAergic interneurons are born in the ganglionic eminence and migrate tangentially. The migration of newly born cortical neurons is tightly regulated by both extracellular and intracellular signaling to ensure proper positioning and projections. Non-cell-autonomous extracellular molecules, such as growth factors, axon guidance molecules, extracellular matrix, and other ligands, play a role in cortical migration, either by acting as attractants or repellents. In this article, we review the guidance molecules that act as cell-cell recognition molecules for the regulation of neuronal migration, with a focus on netrin family proteins, their receptors, and related molecules, including neogenin, repulsive guidance molecules (RGMs), Down syndrome cell adhesion molecule (DSCAM), fibronectin leucine-rich repeat transmembrane proteins (FLRTs), and draxin. Netrin proteins induce attractive and repulsive signals depending on their receptors. For example, binding of netrin-1 to deleted in colorectal cancer (DCC), possibly together with Unc5, repels migrating GABAergic neurons from the ventricular zone of the ganglionic eminence, whereas binding to α3β1 integrin promotes cortical interneuron migration. Human genetic disorders associated with these and related guidance molecules, such as congenital mirror movements, schizophrenia, and bipolar disorder, are also discussed.

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  • While many structural components are pre-assembled, contact-mediated cell-cell communications and guidance cues (e.g., netrins, FLRTs) are essential for proper wiring and synaptic targeting.

    “While many structural components are pre-assembled, contact-mediated cell–cell communications and guidance cues (e.g., netrins, FLRTs) are essential for proper wiring and synaptic targeting [80].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [80]

    The Cortical Neuron Migration and Unc5/FLRT sections describe netrins and FLRTs as guidance and recognition molecules involved in neuronal migration, axon guidance, and synapse formation. The paper does not establish that structural components are pre-assembled or that these cues are essential for synaptic targeting; Future Directions says how they coordinate proper wiring remains poorly understood. No page numbers are available in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The totality of specific molecules and chemical signals involved in guiding initial synapse formation and target specificity is not yet completely understood.

    “The totality of specific molecules and chemical signals involved in guiding initial synapse formation and target specificity is not yet completely understood [46,80,81].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [80]

    The Future Directions section says that synapse formation is among the functions of netrins and that little is known about how these functions are coordinated for proper neuronal wiring. It does not specifically address the full set of molecules and signals governing initial synapse formation or target specificity; its stated uncertainty concerns coordination after neuronal migration. No page number is available in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Microglia play a central role in activity-dependent synapse elimination by engulfing weak or unnecessary synapses.

    “Microglia, the brain’s resident immune cells, play a central role in activity-dependent synapse elimination by engulfing weak or unnecessary synapses [70,80].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [80]

    The Future Directions section mentions synapse formation and plasticity, while the sections on cortical neuronal migration discuss netrins and their receptors. Searches for microglia, synaptic pruning, and engulfment found no passage in our copy addressing microglial elimination of weak or unnecessary synapses; page numbers were unavailable. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

  • The exact nature of the "punishment signals" that propagate from "winner" to "loser" synapses to drive activity-dependent elimination remains largely unknown.

    “The exact nature of the “punishment signals” that propagate from “winner” to “loser” synapses to drive activity-dependent elimination remains largely unknown [46,80,81].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [80]

    The Future Directions section says that little is known about how netrin-related events, including synapse formation and plasticity, are coordinated in axons and dendrites. It does not address punishment signals passing from winner to loser synapses or their role in activity-dependent elimination. Searches for those terms and for synaptic competition found no passage addressing the claim; our copy provides no page numbers. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

  • Synapse elimination is an activity-dependent process where weaker inputs are removed while more active ones are strengthened, a process mediated by synaptic competition in postsynaptic cells.

    “Finally, synapse elimination is an activity-dependent process where weaker inputs are removed while more active ones are strengthened, a process mediated by synaptic competition in postsynaptic cells [46,80,81].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [80]

    The Future Directions section mentions synapse formation and plasticity, but does not describe activity-dependent elimination, the removal of weaker inputs, or competition in postsynaptic cells. Searches for those mechanisms returned no passage in our copy that addresses the claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Authors
Yamagishi, S., Bando, Y., & Sato, K.
Affiliations
Hamamatsu University (JP)
Corresponding author
Yamagishi, Satoru
ORCID
Venue
Frontiers in Cell and Developmental Biology
Publisher
Frontiers Media SA
Published
2021-01-15
Volume
8
Pages
590009-590009
ISSN
2296-634X (ISSN-L)
DOI
10.3389/fcell.2020.590009
PMC
PMC7843923
OpenAlex
W3120016367
Cited by
44
References
119
Citations by year
2026: 4 · 2025: 14 · 2024: 11 · 2023: 4 · 2022: 8 · 2021: 3
FWCI
0.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Takeda Science Foundation
  • Japan Society for the Promotion of Science (20K15914, 20K21499, 17K08512)
  • Hospital Universiti Sains Malaysia
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
netrin, netrin receptors, neuronal migration, cerebral cortex, axon guidance, DCC, alpha3beta1 integrin, cortical plate, neogenin, repulsive guidance molecules, Dscam, Draxin, mirror movements, schizophrenia, bipolar disorder

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