Understanding axon guidance: are we nearly there yet?

Stoeckli, Esther T.

doi:10.1242/dev.151415

Cited by 252 publications

(212 citation statements)

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“…The developing nervous system must generate, organize, and refine billions of neurons and their connections. While molecular guidance cues forge globally precise neuronal connections between distant brain areas ( Stoeckli, 2018 ; Dickson, 2002 ), the organization of local connections is initially coarse and imprecise ( Dhande et al, 2011 ; Kirkby et al, 2013 ; Sretavan and Shatz, 1986 ). Coincident with the refinement of topographic maps, nascent circuits experience bursts of intrinsically generated activity that emerge before sensory systems are fully functional ( Kirkby et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Purinergic signaling in cochlear supporting cells reduces hair cell excitability by increasing the extracellular space

Babola

Kersbergen

Wang

et al. 2019

Preprint

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Neurons in developing sensory pathways exhibit spontaneous bursts of electrical 11 activity that are critical for survival, maturation and circuit refinement. In the auditory system, 12 intrinsically generated activity arises within the cochlea, but the molecular mechanisms that 13 initiate this activity remain poorly understood. We show that burst firing of mouse inner hair cells 14 prior to hearing onset requires P2RY1 autoreceptors expressed by inner supporting cells. P2RY1 15 activation triggers K + efflux and depolarization of hair cells, as well as osmotic shrinkage of 16 supporting cells that dramatically increased the extracellular space and speed of K + 17 redistribution. Pharmacological inhibition or genetic disruption of P2RY1 suppressed neuronal 18 burst firing by reducing K + release, but unexpectedly enhanced their tonic firing, as water 19 resorption by supporting cells reduced the extracellular space, slowing K + clearance. These 20 studies indicate that purinergic signaling in supporting cells regulates hair cell excitability by 21 controlling the volume of the extracellular space. 22 23 Introduction 24The developing nervous system must generate, organize, and refine billions of neurons and their 25 connections. While molecular guidance cues forge globally precise neuronal connections between 26 distant brain areas (Stoeckli, 2018; Dickson, 2002), the organization of local connections is initially 27 coarse and imprecise (Dhande et al., 2011; Kirkby et al., 2013; Sretavan and Shatz, 1986). Coinci-28 dent with the refinement of topographic maps, nascent circuits experience bursts of intrinsically 29 generated activity that emerge before sensory systems are fully functional (Kirkby et al., 2013). 30 This intrinsically generated activity consists of periodic bursts of high frequency firing that pro-31 motes the survival and maturation of neurons in sensory pathways (Blankenship and Feller, 2010; 32 Moody and Bosma, 2005). The precise patterning of this electrical activity appears crucial for re-33 finement of local connections, as its disruption results in improper formation of topographic maps 34 (Antón-Bolaños et al., 2019; Burbridge et al., 2014; Xu et al., 2011) and impaired maturation and 35 specification of sensory neurons (Shrestha et al., 2018; Sun et al., 2018). In all sensory systems 36that have been examined, spontaneous burst firing arises within their respective developing sen-37 sory organs, e.g. retina, olfactory bulb, spindle organ, and cochlea (Blankenship and Feller, 2010). 38 Although the mechanisms that induce spontaneous activity in the developing retina have been ex-39 1 of 26 Manuscript submitted to eLife tensively explored, much less is known about the key steps involved in triggering auditory neuron 40 burst firing in the developing cochlea. Understanding these processes may provide novel insights 41 into the causes of developmental auditory disorders, such as hypersensitivity to sounds and audi-42 tory processing disorders that prevent children from communicating a...

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Section: Introductionmentioning

confidence: 99%

Purinergic signaling in cochlear supporting cells reduces hair cell excitability by increasing the extracellular space

Babola

Kersbergen

Wang

et al. 2019

Preprint

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“…This seems particularly important for morphologically complex cells 35 such as neurons, where the axonal sub-compartment and its tip, the growth cone, often far 36 away from the cell body, can rapidly perform specialized functions (Holt and Schuman, 37 2013). During neuronal wiring, specific interactions between extrinsic cues and receptors 38 mediate guidance of axons to their proper target area, where they also regulate axon 39 branching (Stoeckli, 2018, Manitt et al, 2009, Marshak et al, 2007, Cioni et al, 2013. The 40 rapid axonal responses to several guidance cues require local protein synthesis (Jung et al,41 2012, Campbell and Holt, 2001).…”

Section: Introduction 33mentioning

confidence: 99%

Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons

Koppers

Cagnetta

Shigeoka

et al. 2019

Preprint

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19During neuronal wiring, extrinsic cues trigger the local translation of specific mRNAs in axons 20 via cell surface receptors. The coupling of ribosomes to receptors has been proposed as a 21 mechanism linking signals to local translation but it is not known how broadly this mechanism 22 operates, nor whether it can selectively regulate mRNA translation. We report that receptor-23 ribosome coupling is employed by multiple guidance cue receptors and this interaction is 24 mRNA-dependent. We find that different receptors bind to distinct sets of mRNAs and RNA-25 binding proteins. Cue stimulation induces rapid dissociation of ribosomes from receptors and 26 the selective translation of receptor-specific mRNAs in retinal axon growth cones. Further, 27we show that receptor-ribosome dissociation and cue-induced selective translation are 28 inhibited by simultaneous exposure to translation-repressive cues, suggesting a novel mode 29 of signal integration. Our findings reveal receptor-specific interactomes and provide a general 30 model for the rapid, localized and selective control of cue-induced translation. 31 Lin and Holt, 2008). Unbiased detection of newly synthesized proteins in the axon 47 compartment has revealed further complexity showing that different guidance cues stimulate 48 the regulation of distinct signature sets of >100 axonal nascent proteins within just 5 mins, 49 many of which are not cytoskeletal-related , Yao et al., 2006, Wu et al., 50 2005. However, the mechanisms underlying the 51 localization and selectivity of translation are unclear. Several mechanisms are known to 52 control different aspects of axonal translation, including microRNA regulation (Bellon et al., 53 2017), mRNA modification (Yu et al., 2018), modulation of the phosphorylation of eukaryotic 54 initiation factors (Cagnetta et al., 2019), RNA-binding protein (RBP) phosphorylation (Sasaki 55 et al., 2010, Lepelletier et al., 2017, Huttelmaier et al., 2005) and receptor-ribosome coupling 56 (Tcherkezian et al. , 2010). The latter is a particularly direct and attractive mechanism to link 57 cue-specific signalling to differential mRNA translation. However, this mechanism has been 58 shown only for the Netrin-1 receptor, deleted in colorectal cancer (DCC), in commissural 59 axon growth cones and HEK293 cells (Tcherkezian et al., 2010) and it is unknown whether 60 receptor-ribosome coupling is a widespread mechanism used by different receptors and in 61 different cell types, and whether it regulates selective local translation. 62 63 Here, we show in retinal ganglion cell (RGC) axon growth cones that receptor-ribosome 64 coupling is used by several different axon guidance receptors (DCC, Neuropilin-1 and 65 Robo2), indicative of a common mechanism. Upon stimulation by specific cues, ribosomes 66 dissociate from their receptors within 2 minutes. Interestingly, the receptor-ribosome 67 interaction is mRNA-dependent, and immunoprecipitation (IP) reveals that distinct receptors 68 associate with specific RNA-binding proteins (RBPs) an...

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“…These neurons, which are born embryonically, project their axons contra‐laterally to connect the left and right side of the organism. Together, these commissural networks not only allow for integration and coordination of left‐right neuronal activities, but are essential for the correct processing and interpretation of various sensory information, the coordination of motor responses and other brain functions (Stoeckli ; Gaudet and Fonken ; Ducuing et al ). Many commissural tracts exist in the CNS (Chédotal ).…”

Section: The Developing Nervous Systemmentioning

confidence: 99%

Construction and reconstruction of brain circuits: normal and pathological axon guidance

Roig‐Puiggros

Vigouroux

Beckman

et al. 2019

Journal of Neurochemistry

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Perception of our environment entirely depends on the close interaction between the central and peripheral nervous system. In order to communicate each other, both systems must develop in parallel and in coordination. During development, axonal projections from the CNS as well as the PNS must extend over large distances to reach their appropriate target cells. To do so, they read and follow a series of axon guidance molecules. Interestingly, while these molecules play critical roles in guiding developing axons, they have also been shown to be critical in other major neurodevelopmental processes, such as the migration of cortical progenitors. Currently, a major hurdle for brain repair after injury or neurodegeneration is the absence of axonal regeneration in the mammalian CNS. By contrasts, PNS axons can regenerate. Many hypotheses have been put forward to explain this paradox but recent studies suggest that hacking neurodevelopmental mechanisms may be the key to promote CNS regeneration. Here we provide a seminar report written by trainees attending the second Flagship school held in Alpbach, Austria in September 2018 organized by the International Society for Neurochemistry (ISN) together with the Journal of Neurochemistry (JCN). This advanced school has brought together leaders in the fields of neurodevelopment and regeneration in order to discuss major keystones and future challenges in these respective fields.

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Understanding axon guidance: are we nearly there yet?

Cited by 252 publications

References 140 publications

Purinergic signaling in cochlear supporting cells reduces hair cell excitability by increasing the extracellular space

Purinergic signaling in cochlear supporting cells reduces hair cell excitability by increasing the extracellular space

Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons

Construction and reconstruction of brain circuits: normal and pathological axon guidance

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