Commissural axon guidance in the developing spinal cord: from Cajal to the present day

Abstract During neuronal development, the formation of neural circuits requires developing axons to traverse a diverse cellular and molecular environment to establish synaptic contacts with the appropriate postsynaptic partners. Essential to this process is the ability of developing axons to navigate guidance molecules presented by specialized populations of cells. These cells partition the distance traveled by growing axons into shorter intervals by serving as intermediate targets, orchestrating the arrival and departure of axons by providing attractive and repulsive guidance cues. The floor plate in the central nervous system (CNS) is a critical intermediate target during neuronal development, required for the extension of commissural axons across the ventral midline. In this review, we begin by giving a historical overview of the ventral commissure and the evolutionary purpose of decussation. We then review the axon guidance studies that have revealed a diverse assortment of midline guidance cues, as well as genetic and molecular regulatory mechanisms required for coordinating the commissural axon response to these cues. Finally, we examine the contribution of dysfunctional axon guidance to neurological diseases.

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Dorsal commissural axon guidance in the developing spinal cord

10.1016/bs.ctdb.2020.10.009 ◽

2020 ◽

Author(s):

Sandy Alvarez ◽

Supraja G. Varadarajan ◽

Samantha J. Butler

Keyword(s):

Spinal Cord ◽

Axon Guidance ◽

Commissural Axon ◽

Developing Spinal Cord

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Possible Involvement of TLRs and Hemichannels in Stress-Induced CNS Dysfunction via Mastocytes, and Glia Activation

Mediators of Inflammation ◽

10.1155/2013/893521 ◽

2013 ◽

Vol 2013 ◽

pp. 1-17 ◽

Cited By ~ 20

Author(s):

Adam Aguirre ◽

Carola J. Maturana ◽

Paloma A. Harcha ◽

Juan C. Sáez

Keyword(s):

Glial Cells ◽

Neuronal Development ◽

Viral Infections ◽

Inflammatory Responses ◽

Neurological Diseases ◽

Atp Release ◽

Autism Spectrum ◽

Membrane Pores ◽

The Central Nervous System ◽

Cns Dysfunction

In the central nervous system (CNS), mastocytes and glial cells (microglia, astrocytes and oligodendrocytes) function as sensors of neuroinflammatory conditions, responding to stress triggers or becoming sensitized to subsequent proinflammatory challenges. The corticotropin-releasing hormone and glucocorticoids are critical players in stress-induced mastocyte degranulation and potentiation of glial inflammatory responses, respectively. Mastocytes and glial cells express different toll-like receptor (TLR) family members, and their activation via proinflammatory molecules can increase the expression of connexin hemichannels and pannexin channels in glial cells. These membrane pores are oligohexamers of the corresponding protein subunits located in the cell surface. They allow ATP release and Ca2+influx, which are two important elements of inflammation. Consequently, activated microglia and astrocytes release ATP and glutamate, affecting myelinization, neuronal development, and survival. Binding of ligands to TLRs induces a cascade of intracellular events leading to activation of several transcription factors that regulate the expression of many genes involved in inflammation. During pregnancy, the previous responses promoted by viral infections and other proinflammatory conditions are common and might predispose the offspring to develop psychiatric disorders and neurological diseases. Such disorders could eventually be potentiated by stress and might be part of the etiopathogenesis of CNS dysfunctions including autism spectrum disorders and schizophrenia.

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Gradient-reading and mechano-effector machinery for netrin-1-induced axon guidance

eLife ◽

10.7554/elife.34593 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 7

Author(s):

Kentarou Baba ◽

Wataru Yoshida ◽

Michinori Toriyama ◽

Tadayuki Shimada ◽

Colleen F Manning ◽

...

Keyword(s):

Cell Adhesion ◽

Axon Guidance ◽

Cell Adhesion Molecule ◽

Growth Cones ◽

Spatial Cues ◽

Commissural Axons ◽

Guidance Cues ◽

Cell Adhesion Molecule L1 ◽

Axon Guidance Molecule ◽

Guidance Molecule

Growth cones navigate axonal projection in response to guidance cues. However, it is unclear how they can decide the migratory direction by transducing the local spatial cues into protrusive forces. Here we show that knockout mice of Shootin1 display abnormal projection of the forebrain commissural axons, a phenotype similar to that of the axon guidance molecule netrin-1. Shallow gradients of netrin-1 elicited highly polarized Pak1-mediated phosphorylation of shootin1 within growth cones. We demonstrate that netrin-1–elicited shootin1 phosphorylation increases shootin1 interaction with the cell adhesion molecule L1-CAM; this, in turn, promotes F-actin–adhesion coupling and concomitant generation of forces for growth cone migration. Moreover, the spatially regulated shootin1 phosphorylation within growth cones is required for axon turning induced by netrin-1 gradients. Our study defines a mechano-effector for netrin-1 signaling and demonstrates that shootin1 phosphorylation is a critical readout for netrin-1 gradients that results in a directional mechanoresponse for axon guidance.

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Commissureless is required both in commissural neurones and midline cells for axon guidance across the midline

Development ◽

10.1242/dev.129.12.2947 ◽

2002 ◽

Vol 129 (12) ◽

pp. 2947-2956 ◽

Cited By ~ 1

Author(s):

Marios Georgiou ◽

Guy Tear

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Rna Interference ◽

Protein Expression ◽

Axon Guidance ◽

Contralateral Side ◽

Commissural Axons ◽

Midline Crossing ◽

The Central Nervous System ◽

Midline Cells

In the absence of Commissureless (Comm) function, axons are unable to extend across the central nervous system midline. Comm downregulates levels of Roundabout (Robo), a receptor for the midline repellent Slit, in order to allow axons to cross the midline. comm transcript is expressed at high levels in the midline glia and Comm protein accumulates on axons at the midline. This has led to the hypothesis that Comm moves from the midline glia to the axons, where it can reduce Robo levels. We have found that expression of Comm in the midline cells is unable to rescue the comm phenotype and that tagged versions of Comm are not transferred to axons. A re-examination of Comm protein expression and the use of targeted RNA interference reveal that correct midline crossing requires that Comm is expressed in the commissural axons and midline glia. We suggest that accumulation of Comm protein at the midline spatially limits Comm activity and prevents it from being active on the contralateral side of the central nervous system.

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Unraveling Axon Guidance during Axotomy and Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms22158344 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8344

Author(s):

Miguel E. Domínguez-Romero ◽

Paula G. Slater

Keyword(s):

Nervous System ◽

Growth Cone ◽

Neuronal Development ◽

System Development ◽

Nervous System Development ◽

Signaling Cascades ◽

Final Destination ◽

Guidance Cues ◽

The Central Nervous System ◽

Do So

During neuronal development and regeneration axons extend a cytoskeletal-rich structure known as the growth cone, which detects and integrates signals to reach its final destination. The guidance cues “signals” bind their receptors, activating signaling cascades that result in the regulation of the growth cone cytoskeleton, defining growth cone advance, pausing, turning, or collapse. Even though much is known about guidance cues and their isolated mechanisms during nervous system development, there is still a gap in the understanding of the crosstalk between them, and about what happens after nervous system injuries. After neuronal injuries in mammals, only axons in the peripheral nervous system are able to regenerate, while the ones from the central nervous system fail to do so. Therefore, untangling the guidance cues mechanisms, as well as their behavior and characterization after axotomy and regeneration, are of special interest for understanding and treating neuronal injuries. In this review, we present findings on growth cone guidance and canonical guidance cues mechanisms, followed by a description and comparison of growth cone pathfinding mechanisms after axotomy, in regenerative and non-regenerative animal models.

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Semaphorins: a new class of immunoregulatory molecules

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2005.1696 ◽

2005 ◽

Vol 360 (1461) ◽

pp. 1673-1680 ◽

Cited By ~ 31

Author(s):

Noriko Takegahara ◽

Atsushi Kumanogoh ◽

Hitoshi Kikutani

Keyword(s):

Immune System ◽

Immune Responses ◽

Axon Guidance ◽

Neuronal Development ◽

Normal Function ◽

Immune Functions ◽

New Class ◽

Guidance Cues ◽

Physiological Homeostasis ◽

Neuronal Guidance

The immune and nervous systems play distinct roles in maintaining physiological homeostasis. Recent data indicates that these systems influence one another and share many proteins and pathways that are essential for their normal function and development. Molecules originally shown to be critical for the development of proper immune responses have recently been found to function in the nervous system. Conversely, neuronal guidance cues can modulate immune functions. Although semaphorins were originally identified as axon guidance factors active during neuronal development, several recent studies have identified indispensable functions for these molecules in the immune system. This review provides an overview of the rapidly emerging functions of semaphorins and their receptors in the immune system.

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Mills' syndrome. A clinical case of a rare degenerative pathology of the central nervous system

Spravočnik vrača obŝej praktiki (Journal of Family Medicine) ◽

10.33920/med-10-2004-07 ◽

2020 ◽

pp. 57-60

Author(s):

Konstantin Gulyabin

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neurological Diseases ◽

Cortical Atrophy ◽

Primary Lateral Sclerosis ◽

System A ◽

The Central Nervous System ◽

Primary Lateral ◽

Lateral Sclerosis ◽

Mills Syndrome

Mills' syndrome is a rare neurological disorder. Its nosological nature is currently not completely determined. Nevertheless, Mills' syndrome is considered to be a rare variant of the degenerative pathology of the central nervous system – a variant of focal cortical atrophy. The true prevalence of this pathology is unknown, since this condition is more often of a syndrome type, observed in the clinical picture of a number of neurological diseases (primary lateral sclerosis, frontotemporal dementia, etc.) and is less common in isolated form.

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