A new model for netrin1 in commissural axon guidance

Morales, Daniel

doi:10.1002/jnr.24117

Cited by 10 publications

(10 citation statements)

References 31 publications

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“…One current model suggests that the pial-netrin-1 substrate acts by haptotaxis to promote commissural axon extension and direct axons toward the ventral midline. Other excellent papers detailed the functions of netrin-1 in guiding the commissural axons to the ventral midline ( Morales, 2018 ; Chedotal, 2019 ; Comer et al, 2019 ; Ducuing et al, 2019 ). Importantly, draxin is also heavily deposited in the basement membrane along the dorsal and lateral sides of the spinal cord ( Figure 2A ; Islam et al, 2009 ), suggesting a role of pial-draxin in commissural axon guidance.…”

Section: Spinal Commissural Axonsmentioning

confidence: 99%

Multiple Functions of Draxin/Netrin-1 Signaling in the Development of Neural Circuits in the Spinal Cord and the Brain

Ahmed

Shinmyo

2021

Front. Neuroanat.

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Axon guidance proteins play key roles in the formation of neural circuits during development. We previously identified an axon guidance cue, named draxin, that has no homology with other axon guidance proteins. Draxin is essential for the development of various neural circuits including the spinal cord commissure, corpus callosum, and thalamocortical projections. Draxin has been shown to not only control axon guidance through netrin-1 receptors, deleted in colorectal cancer (Dcc), and neogenin (Neo1) but also modulate netrin-1-mediated axon guidance and fasciculation. In this review, we summarize the multifaceted functions of draxin and netrin-1 signaling in neural circuit formation in the central nervous system. Furthermore, because recent studies suggest that the distributions and functions of axon guidance cues are highly regulated by glycoproteins such as Dystroglycan and Heparan sulfate proteoglycans, we discuss a possible function of glycoproteins in draxin/netrin-1-mediated axon guidance.

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Section: Spinal Commissural Axonsmentioning

confidence: 99%

Multiple Functions of Draxin/Netrin-1 Signaling in the Development of Neural Circuits in the Spinal Cord and the Brain

Ahmed

Shinmyo

2021

Front. Neuroanat.

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“…The original studies on the function of netrin-1 in vivo relied on a hypomorphic gene trap allele of Ntn1 that maintained low levels of netrin-1 protein ( Serafini et al, 1996 ), however, recent development of mice carrying a floxed Ntn1 allele has allowed for tissue-specific and complete loss of netrin-1 ( Bin et al, 2015 ; Yung et al, 2015 ). Three recent papers have galvanized the potential role of netrin-1 as a haptotactic cue in vivo by selectively deleting netrin-1 from the floor plate and/or ventricular zone of the spine and hindbrain using floxed Ntn1 alleles, and assessing the midline crossing of commissural axons ( Dominici et al, 2017 ; Varadarajan et al, 2017 ; Yamauchi et al, 2017 ) (for an additional mini-review on Dominici et al and Varadarajan et al, see Morales, 2018 ). All three groups found that netrin-1 expression in the floor plate, originally thought to be the source of the attractive gradient of netrin-1 responsible for commissural crossing ( Maclennan et al, 1997 ; Kennedy et al, 2006 ), is not necessary for commissure formation.…”

Section: Netrin-1 the Classical Guidance Cuementioning

confidence: 99%

Revisiting Netrin-1: One Who Guides (Axons)

Boyer¹,

Gupton²

2018

Front. Cell. Neurosci.

143

130

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Proper patterning of the nervous system requires that developing axons find appropriate postsynaptic partners; this entails microns to meters of extension through an extracellular milieu exhibiting a wide range of mechanical and chemical properties. Thus, the elaborate networks of fiber tracts and non-fasciculated axons evident in mature organisms are formed via complex pathfinding. The macroscopic structures of axon projections are highly stereotyped across members of the same species, indicating precise mechanisms guide their formation. The developing axon exhibits directionally biased growth toward or away from external guidance cues. One of the most studied guidance cues is netrin-1, however, its presentation in vivo remains debated. Guidance cues can be secreted to form soluble or chemotactic gradients or presented bound to cells or the extracellular matrix to form haptotactic gradients. The growth cone, a highly specialized dynamic structure at the end of the extending axon, detects these guidance cues via transmembrane receptors, such as the netrin-1 receptors deleted in colorectal cancer (DCC) and UNC5. These receptors orchestrate remodeling of the cytoskeleton and cell membrane through both chemical and mechanotransductive pathways, which result in traction forces generated by the cytoskeleton against the extracellular environment and translocation of the growth cone. Through intracellular signaling responses, netrin-1 can trigger either attraction or repulsion of the axon. Here we review the mechanisms by which the classical guidance cue netrin-1 regulates intracellular effectors to respond to the extracellular environment in the context of axon guidance during development of the central nervous system and discuss recent findings that demonstrate the critical importance of mechanical forces in this process.

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“…Classically, Netrin was thought to establish a ventral-to-dorsal gradient, which was followed by growth cones growing up the gradient (attraction) or down the gradient (repulsion) (SERAFINI et al 1996;FAZELI et al 1997;KENNEDY et al 2006). Recent studies in vertebrate spinal cord and our studies in C. elegans suggest a distinct mechanism (DOMINICI et al 2017;VARADARAJAN et al 2017;YAMAUCHI et al 2017;MORALES 2018). In the spinal cord, floorplate Netrin1 was found to be dispensable for ventral commissural axon guidance.…”

Section: Introductionmentioning

confidence: 55%

The PH/MyTH4/FERM molecule MAX-1 inhibits UNC-5 activity in regulation of VD growth cone protrusion in Caenorhabditis elegans

Mahadik

Lundquist

2021

Preprint

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UNC-6/Netrin is a secreted conserved guidance cue that regulates dorsal-ventral axon guidance of C. elegans and in the vertebral spinal cord. In the polarity/protrusion model of VD growth cone guidance away from ventrally-expressed UNC-6 (repulsion), UNC-6 first polarizes the growth cone via the UNC-5 receptor such that filopodial protrusions are biased dorsally. UNC-6 then regulates a balance of protrusion in the growth cone based upon this polarity. UNC-5 inhibits protrusion ventrally, and the UNC-6 receptor UNC-40/DCC stimulates protrusion dorsally, resulting in net dorsal growth cone outgrowth. UNC-5 inhibits protrusion through the flavin monooxygenases FMO-1, 4, and 5 and possible actin destabilization, and inhibits pro-protrusive microtubule entry into the growth cone utilizing UNC-33/CRMP. The PH/MyTH4/FERM myosin-like protein was previously shown to act with UNC-5 in VD axon guidance utilizing axon guidance endpoint analysis. Here, we analyzed the effects of MAX-1 on VD growth cone morphology during outgrowth. We found that max-1 mutant growth cones were smaller and less protrusive than wild-type, the opposite of the unc-5 mutant phenotype. Furthermore, genetic interactions suggest that MAX-1 might normally inhibit UNC-5 activity, such that in a max-1 mutant growth cone, UNC-5 is overactive. Our results, combined with previous studies suggesting that MAX-1 might regulate UNC-5 levels in the cell or plasma membrane localization, suggest that MAX-1 attenuates UNC-5 signaling by regulating UNC-5 stability or trafficking. In summary, in the context of growth cone protrusion, MAX-1 inhibits UNC-5, demonstrating the mechanistic insight that can be gained by analyzing growth cones during outgrowth in addition to axon guidance endpoint analysis.

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A new model for netrin1 in commissural axon guidance

Cited by 10 publications

References 31 publications

Multiple Functions of Draxin/Netrin-1 Signaling in the Development of Neural Circuits in the Spinal Cord and the Brain

Multiple Functions of Draxin/Netrin-1 Signaling in the Development of Neural Circuits in the Spinal Cord and the Brain

Revisiting Netrin-1: One Who Guides (Axons)

The PH/MyTH4/FERM molecule MAX-1 inhibits UNC-5 activity in regulation of VD growth cone protrusion in Caenorhabditis elegans

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