Motor axon navigation relies on Fidgetin-like 1–driven microtubule plus end dynamics

Fassier, Coralie; Fréal, Amélie; Gasmi, Laïla; Delphin, Christian; Martín, Daniel Ten; Gois, Stéphanie De; Tambalo, Monica; Bosc, Christophe; Mailly, Philippe; Revenu, Céline; Peris, Leticia; Bolte, Susanne; Schneider‐Maunoury, Sylvie; Houart, Corinne; Nothias, Fatiha; Larcher, Jean-Christophe; Andrieux, Annie; Hazan, Jamilé

doi:10.1083/jcb.201604108

Cited by 30 publications

(52 citation statements)

References 97 publications

(122 reference statements)

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“…Altogether, these results revealed a dose-effect impact of Fignl1 on RoP-like sMN development (Fig. 3, F–H) and strengthened our morpholino data (Fassier et al, 2018).…”

Section: Resultssupporting

confidence: 86%

“…However, kif1b st43 mutants showed sMN axon pathfinding defects, which were restricted to rostrally projecting-like sMN (RoP-like sMN; Fig. 3, A–D) and overlapped the RoP-like sMN defects observed in mildly affected Fignl1 morphants (i.e., embryos injected with Fignl1 morpholino; Fassier et al, 2018) and fignl1 sa22254 mutants—harboring a mutation that results in the truncation of the ATPase domain (Fig. 3 E).…”

Section: Resultsmentioning

confidence: 99%

“…Our team has recently identified the ATPase Fidgetin-like 1 (Fignl1) as a key player in zebrafish motor circuit wiring, via its regulation of MT plus-end dynamics (Fassier et al, 2018). Here, we report on a new role for Fignl1 in zebrafish axon navigation, via its regulation of bidirectional axonal vesicular trafficking.…”

Section: Introductionmentioning

confidence: 99%

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FIGNL1 associates with KIF1Bβ and BICD1 to restrict dynein transport velocity during axon navigation

Atkins

Gasmi

Bercier

et al. 2019

Journal of Cell Biology

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Neuronal connectivity relies on molecular motor-based axonal transport of diverse cargoes. Yet the precise players and regulatory mechanisms orchestrating such trafficking events remain largely unknown. We here report the ATPase Fignl1 as a novel regulator of bidirectional transport during axon navigation. Using a yeast two-hybrid screen and coimmunoprecipitation assays, we showed that Fignl1 binds the kinesin Kif1bβ and the dynein/dynactin adaptor Bicaudal D-1 (Bicd1) in a molecular complex including the dynactin subunit dynactin 1. Fignl1 colocalized with Kif1bβ and showed bidirectional mobility in zebrafish axons. Notably, Kif1bβ and Fignl1 loss of function similarly altered zebrafish motor axon pathfinding and increased dynein-based transport velocity of Rab3 vesicles in these navigating axons, pinpointing Fignl1/Kif1bβ as a dynein speed limiter complex. Accordingly, disrupting dynein/dynactin activity or Bicd1/Fignl1 interaction induced motor axon pathfinding defects characteristic of Fignl1 gain or loss of function, respectively. Finally, pharmacological inhibition of dynein activity partially rescued the axon pathfinding defects of Fignl1-depleted larvae. Together, our results identify Fignl1 as a key dynein regulator required for motor circuit wiring.

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“…Altogether, these results revealed a dose-effect impact of Fignl1 on RoP-like sMN development (Fig. 3, F–H) and strengthened our morpholino data (Fassier et al, 2018).…”

Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

FIGNL1 associates with KIF1Bβ and BICD1 to restrict dynein transport velocity during axon navigation

Atkins

Gasmi

Bercier

et al. 2019

Journal of Cell Biology

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“…MT severing enzymes include katanin, spastin, and the fidgetin family (fidgetin, fidgetin-like 1 (FL1), and fidgetin-like 2 (FL2)). With the exception of FL2, all have been reported to play important roles in regulating axonal growth through their remodeling of the axonal MT array [9,[15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Fidgetin-like 2 is a novel negative regulator of axonal growth and can be targeted to promote functional nerve regeneration after injury

Baker

Tar

Villegas

et al. 2020

Preprint

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The microtubule (MT) cytoskeleton plays a critical role in axon growth and guidance. Here, we identify the MT severing enzyme fidgetin-like 2 (FL2) as a negative regulator of axonal regeneration and a potential therapeutic target for promoting neural regeneration after injury.Genetic knockout of FL2 in cultured adult dorsal root ganglion (DRG) neurons resulted in longer axons and attenuated growth cone retraction in response to inhibitory molecules. Given the axonal growth-promoting effects of FL2 depletion in vitro, we tested whether the enzyme could be targeted to promote regeneration in a rodent model of peripheral nerve injury. In the model used in our experiments, the cavernous nerves (CN) are either crushed or transected, mimicking nerve injury caused by radical prostatectomy (RP). As with patients, CN injury results in erectile dysfunction, for which there are presently poor treatment options. At the time of injury, FL2-siRNA or control-siRNA was applied to the site using nanoparticles or chondroitin sulfate microgels as delivery agents. Treatment significantly enhanced functional nerve recovery, as determined by cavernosometry (measurements of corporal blood pressure in response to electrostimulation of the nerve). Remarkably, following complete bilateral nerve transection, visible and functional nerve regeneration was observed in 7 out of 8 animals treated with FL2-siRNA. In contrast, no control-siRNA treated animals showed regeneration. These observations suggest a novel therapeutic approach to treat peripheral nerve injury, particularly injuries resulting from surgical procedures such as RP, where treatments depleting FL2 could be applied locally at the time of injury.

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“…However, very little is known about how the direction of growth of plus ends, and therefore the orientation of MTs, is controlled in cells. In axons, adenomatous polyposis coli (APC) seems to regulate plus end direction (Purro et al ., 2008), while Fidgetin-like1, a MT-associated ATPase, controls both dynamics and plus ends direction (Fassier et al ., 2018). MT bending also impacts on the direction of plus tip growth, as the MT tip rotates due to local bend formation (Kent et al ., 2016).…”

Section: Introductionmentioning

confidence: 99%

Optical flow analysis reveals that Kinesin-mediated advection impacts on the orientation of microtubules in theDrosophilaoocyte

Drechsler

Lang

al-Khatib

et al. 2019

Preprint

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21The polar orientation of microtubule networks is exploited by molecular motors, such as kinesins, to 22 deliver cargoes to specific intracellular destinations, and is thus essential for cell polarity and cell 23 function. Reconstituted in vitro systems have largely contributed to the current understanding of the 24 molecular framework, regulating the behaviour of single microtubule filaments. In cells however, 25 microtubules are subjected to a variety of different biomechanical forces that might impact on their 26 orientation and thus on the organisation of the entire network. Here we implement variational optical 27 flow analysis as a new approach to analyse the polarity of microtubule networks in vivo, and find that 28 cytoplasmic flows impact on the growth direction of microtubule plus ends in the Drosophila oocyte. 29We provide a thorough characterisation of microtubule behaviour and orientation under different 30 kinesin-dependent cytoplasmic flow conditions, and establish that flows are sufficient and necessary 31 to support the overall organisation of the microtubule cytoskeleton. Introduction 33Eukaryotic life depends on many dynamic processes, including for example cell division, cell 34 migration, and cell polarisation. These processes in turn strongly rely on highly organised 35 microtubule (MT) arrays. All MT networks are polarised, with the minus end of each filament linked 36 to a nucleating centre (MT organising centre or MTOC), and the plus end growing away from these 37 centres. This intrinsic polarity is utilised by specific motor proteins to transport cargo along MTs in a 38 defined direction, and is essential for the function of MT networks, and consequently for the function 39 and polarity of cells. 40A number of biophysical studies in reconstituted in vitro systems have helped to understand the 41 mechanical properties of MTs, setting the stage to investigate the behaviour of MTs in vivo. However, 42 much needs to be learnt about the properties of MTs in their natural intracellular environment. For 43 example, a rather new concept emanating from in vivo experiments is that controlling nucleation and 44 the position of minus ends alone is not always sufficient to establish the proper polarity of the 45 network. Thus MT plus ends must be controlled as well in order to allow motor proteins to deliver 46 their cargoes to the correct destination. The plus ends can be regulated at various levels, including 47 dynamic instability, capturing, and direction of growth. Dynamic instability describes a process, in 48 which MT polymerisation is interrupted by a rapid depolymerisation phase, followed by a 'rescue' 49 process 1 . Various MT-associated proteins, such as molecular motors and MT plus end-tracking 50 proteins (+TIPs), are known to regulate dynamic instability 2 . Furthermore, MT plus ends can also be 51 stabilised by cortical capture, also involving +TIPs and other molecules such as the Dynein/Dynactin 52 complex 3 (and as reviewed in 2 ). However, very little is known about how the directi...

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Motor axon navigation relies on Fidgetin-like 1–driven microtubule plus end dynamics

Cited by 30 publications

References 97 publications

FIGNL1 associates with KIF1Bβ and BICD1 to restrict dynein transport velocity during axon navigation

FIGNL1 associates with KIF1Bβ and BICD1 to restrict dynein transport velocity during axon navigation

Fidgetin-like 2 is a novel negative regulator of axonal growth and can be targeted to promote functional nerve regeneration after injury

Optical flow analysis reveals that Kinesin-mediated advection impacts on the orientation of microtubules in theDrosophilaoocyte

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