The UNC-6/Netrin receptors UNC-40/DCC and UNC-5 inhibit growth cone filopodial protrusion via UNC-73/Trio, Rac-like GTPases and UNC-33/CRMP

Norris, Adam; Sundararajan, Lakshmi; Morgan, Dyan E.; Roberts, Zachary J.; Lundquist, Erik A.

doi:10.1242/dev.110437

Cited by 47 publications

(183 citation statements)

References 65 publications

(112 reference statements)

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“…Our findings suggest that this different responsiveness within the same cells can also be mediated by the local activation of distinct GEFs. In C. elegans PDE neurons, for example, TIAM-1 regulates growth cone extension via Rac GTPases responding to the activated netrin receptor UNC-40/DCC (33), whereas UNC-73 inhibits this extension (49). Importantly, lowering the levels of mig-2 and ced-10 causes migrating cells to be repulsed rather than attracted to Semaphorin-1 and Plexin-1 (50), suggesting that the proper activity of Rho family GTPases is critical for the response to cues.…”

Section: Discussionmentioning

confidence: 99%

GEFs and Rac GTPases control directional specificity of neurite extension along the anterior–posterior axis

Zheng

Diaz‐Cuadros

Chalfie

2016

Proc. Natl. Acad. Sci. U.S.A.

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Although previous studies have identified many extracellular guidance molecules and intracellular signaling proteins that regulate axonal outgrowth and extension, most were conducted in the context of unidirectional neurite growth, in which the guidance cues either attract or repel growth cones. Very few studies addressed how intracellular signaling molecules differentially specify bidirectional outgrowth. Here, using the bipolar PLM neurons in Caenorhabditis elegans, we show that the guanine nucleotide exchange factors (GEFs) UNC-73/Trio and TIAM-1 promote anterior and posterior neurite extension, respectively. The Rac subfamily GTPases act downstream of the GEFs; CED-10/Rac1 is activated by TIAM-1, whereas CED-10 and MIG-2/RhoG act redundantly downstream of UNC-73. Moreover, these two pathways antagonize each other and thus regulate the directional bias of neuritogenesis. Our study suggests that directional specificity of neurite extension is conferred through the intracellular activation of distinct GEFs and Rac GTPases. 2). Although several signaling cascades connect the activation of various ligand-bound receptors to the remodeling of the actin and microtubule cytoskeletons, they do so through similar second messengers (i.e., kinases, phosphatases, GTPases) (3, 4) and thus do not address how the directed outgrowth of multiple neurites occurs. Presumably, distinct intracellular pathways mediate neurite outgrowth and extension in different directions, but what these pathways are remains unclear.One potential means of regulating differential outgrowth is the use of the many members of the Rho family of small GTPases [Rac (including Rac1, Rac2, Rac3, and RhoG), Cdc42, and Rho] and the guanine nucleotide exchange factors (GEFs) that activate these GTPases (5). Studies using in vitro cultured mammalian neurons suggest that Rac1 (activated by the GEFs Tiam1 and Dock180), RhoG (activated by the first GEF domain of Trio), and Cdc42 promote axonal outgrowth and extension by regulating the actin and microtubule cytoskeleton (6, 7). In vivo studies in Drosophila and Caenorhabditis elegans suggest that Rac GTPases have overlapping functions in the control of axon growth and guidance and that the Trio GEF is essential for Rac activities in the nervous system (8-10). In contrast, Rho and its downstream effector ROCK negatively regulate axon growth in mammals (11, 12) and suppress dendritic extension in Drosophila (13).Although some studies suggest that small GTPases and GEFs may have different effects on axonal and dendritic growth (14-16), virtually no study has addressed the directional specificity of those signaling molecules for neurites with similar properties in the context of bidirectional growth. Here, we use the bipolar PLM neurons in C. elegans to investigate this question. The posteriorly located, bilaterally symmetric PLM neurons are two of the six mechanosensory touch receptor neurons (TRNs) (17). The PLM neurons have two sensory neurites that grow under different directions; both contain the MEC-4 transducti...

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Section: Discussionmentioning

confidence: 99%

GEFs and Rac GTPases control directional specificity of neurite extension along the anterior–posterior axis

Zheng

Diaz‐Cuadros

Chalfie

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The role that a particular molecule is observed to play in outgrowth may depend on the context under which the system is observed. For example, guidance receptor accumulation and distribution appear to be affected by MIG-2 (RhoG) and UNC-73 (TRIO) activity in some neurons (Levy-Strumpf and Culotti 2007;WatariGoshima et al 2007), but not in others (Norris et al 2014).…”

Section: Regulation Of the Actin Cytoskeleton In Axon Outgrowthmentioning

confidence: 99%

The Genetics of Axon Guidance and Axon Regeneration in Caenorhabditis elegans

Chisholm¹,

Hutter

Jin

et al. 2016

Genetics

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The correct wiring of neuronal circuits depends on outgrowth and guidance of neuronal processes during development. In the past two decades, great progress has been made in understanding the molecular basis of axon outgrowth and guidance. Genetic analysis in Caenorhabditis elegans has played a key role in elucidating conserved pathways regulating axon guidance, including Netrin signaling, the slit Slit/Robo pathway, Wnt signaling, and others. Axon guidance factors were first identified by screens for mutations affecting animal behavior, and by direct visual screens for axon guidance defects. Genetic analysis of these pathways has revealed the complex and combinatorial nature of guidance cues, and has delineated how cues guide growth cones via receptor activity and cytoskeletal rearrangement. Several axon guidance pathways also affect directed migrations of non-neuronal cells in C. elegans, with implications for normal and pathological cell migrations in situations such as tumor metastasis. The small number of neurons and highly stereotyped axonal architecture of the C. elegans nervous system allow analysis of axon guidance at the level of single identified axons, and permit in vivo tests of prevailing models of axon guidance. C. elegans axons also have a robust capacity to undergo regenerative regrowth after precise laser injury (axotomy). Although such axon regrowth shares some similarities with developmental axon outgrowth, screens for regrowth mutants have revealed regenerationspecific pathways and factors that were not identified in developmental screens. Several areas remain poorly understood, including how major axon tracts are formed in the embryo, and the function of axon regeneration in the natural environment. KEYWORDS netrin; semaphorin; ephrin; Wnt; Slit; Robo; fasciculation; DLK; growth cone; actin; microtubule; WormBook

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“…Since GFP expression levels and GFP distribution in individual growth cones are quite variable, we found it difficult to determine whether there are more subtle changes in UNC-5::GFP expression levels. Furthermore the UNC-5::GFP reporter is mainly localized in puncta (likely vesicles) within the growth cone and not localized to the plasma membrane as expected and as observed with an UNC-40::GFP reporter (Norris et al 2014). It is therefore impossible to judge with this reporter whether insertion of UNC-5::GFP into the plasma membrane of growth cones is affected in aex-3 mutant animals.…”

Section: Aex-3 Might Act Through the Netrin Receptor Unc-5mentioning

confidence: 65%

“…This raises the possibility that AEX-3 is involved in the transport of vesicles carrying UNC-5 to the growth cone. An UNC-5::GFP reporter appears in punctate form in growth cones and axons, suggesting localization to vesicles (Ogura and Goshima 2006;Norris et al 2014). UNC-51, a serine/threonine kinase and UNC-14, a RUN (RPIP8, UNC-14, and NESCA) domain-containing protein have been proposed to cooperate with an unknown motor protein to regulate the formation, processing, and transport of UNC-5-containing vesicles (Ogura and Goshima 2006).…”

Section: Discussionmentioning

confidence: 99%

Pioneer Axon Navigation Is Controlled by AEX-3, a Guanine Nucleotide Exchange Factor for RAB-3 in Caenorhabditis elegans

Bhat¹,

Hutter

2016

Genetics

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Precise and accurate axon tract formation is an essential aspect of brain development. This is achieved by the migration of early outgrowing axons (pioneers) allowing later outgrowing axons (followers) to extend toward their targets in the embryo. In Caenorhabditis elegans the AVG neuron pioneers the right axon tract of the ventral nerve cord, the major longitudinal axon tract. AVG is essential for the guidance of follower axons and hence organization of the ventral nerve cord. In an enhancer screen for AVG axon guidance defects in a nid-1/Nidogen mutant background, we isolated an allele of aex-3. aex-3 mutant animals show highly penetrant AVG axon navigation defects. These defects are dependent on a mutation in nid-1/Nidogen, a basement membrane component. Our data suggest that AEX-3 activates RAB-3 in the context of AVG axon navigation. aex-3 genetically acts together with known players of vesicular exocytosis: unc-64/Syntaxin, unc-31/CAPS, and ida-1/IA-2. Furthermore our genetic interaction data suggest that AEX-3 and the UNC-6/Netrin receptor UNC-5 act in the same pathway, suggesting AEX-3 might regulate the trafficking and/or insertion of UNC-5 at the growth cone to mediate the proper guidance of the AVG axon.

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The UNC-6/Netrin receptors UNC-40/DCC and UNC-5 inhibit growth cone filopodial protrusion via UNC-73/Trio, Rac-like GTPases and UNC-33/CRMP

Cited by 47 publications

References 65 publications

GEFs and Rac GTPases control directional specificity of neurite extension along the anterior–posterior axis

GEFs and Rac GTPases control directional specificity of neurite extension along the anterior–posterior axis

The Genetics of Axon Guidance and Axon Regeneration in Caenorhabditis elegans

Pioneer Axon Navigation Is Controlled by AEX-3, a Guanine Nucleotide Exchange Factor for RAB-3 in Caenorhabditis elegans

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