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UNC-6 (netrin) stabilizes oscillatory clustering of the UNC-40 (DCC) receptor to orient polarity.

Wang Z, Linden LM, Naegeli KM, Ziel JW, Chi Q, Hagedorn EJ, Savage NS, Sherwood DR - J. Cell Biol. (2014)

Bottom Line: By performing live-cell imaging of the DCC orthologue UNC-40 during anchor cell invasion in Caenorhabditis elegans, we have found that UNC-40 clusters, recruits F-actin effectors, and generates F-actin in the absence of UNC-6 (netrin).Together, our data suggest that UNC-6 (netrin) directs polarized responses by stabilizing UNC-40 clustering.We propose that ligand-independent UNC-40 clustering provides a robust and adaptable mechanism to polarize toward netrin.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Duke University, Durham, NC 27708.

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A model for UNC-40 (DCC)–mediated polarization toward UNC-6 (netrin). (A) In the absence of UNC-6, UNC-40 (DCC) undergoes oscillations in clustering (polarization). Positive feedback and competition mediates growth and dominance of a single UNC-40/F-actin cluster (middle). Cluster growth then leads to a delayed form of negative feedback (right, black cross) that breaks apart the cluster. After dissipation of negative feedback, the cycle repeats. (B, left) UNC-6 (netrin) in contact with UNC-40 (DCC) at the cell surface counteracts negative feedback, orienting and stabilizing polarity. (middle) Loss of the initial source of netrin leads to breakdown of polarity via negative feedback. (middle, right) A new source of netrin rapidly reorients and stabilizes polarity in a different location by countering negative feedback.
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fig9: A model for UNC-40 (DCC)–mediated polarization toward UNC-6 (netrin). (A) In the absence of UNC-6, UNC-40 (DCC) undergoes oscillations in clustering (polarization). Positive feedback and competition mediates growth and dominance of a single UNC-40/F-actin cluster (middle). Cluster growth then leads to a delayed form of negative feedback (right, black cross) that breaks apart the cluster. After dissipation of negative feedback, the cycle repeats. (B, left) UNC-6 (netrin) in contact with UNC-40 (DCC) at the cell surface counteracts negative feedback, orienting and stabilizing polarity. (middle) Loss of the initial source of netrin leads to breakdown of polarity via negative feedback. (middle, right) A new source of netrin rapidly reorients and stabilizes polarity in a different location by countering negative feedback.

Mentions: The mechanism by which the receptor UNC-40 (DCC) polarizes toward its ligand UNC-6 (netrin) to mediate diverse guidance functions is poorly understood. Using C. elegans AC invasion as a model for UNC-40/UNC-6 polarization, we have found that in the absence of UNC-6, UNC-40 is active, generates F-actin, and undergoes oscillatory clustering characterized by repeated cycles of cluster assembly and disassembly at different regions of the cell surface. We show that UNC-6 orients and stabilizes UNC-40 clustering, and that the protein MADD-2, a direct regulator of UNC-40, promotes UNC-40 clustering and the ability of UNC-40 to polarize toward UNC-6. Together, our data suggest that UNC-6 (netrin) directs polarized responses by stabilizing the localization of oscillatory clustering of the DCC receptor (Fig. 9).


UNC-6 (netrin) stabilizes oscillatory clustering of the UNC-40 (DCC) receptor to orient polarity.

Wang Z, Linden LM, Naegeli KM, Ziel JW, Chi Q, Hagedorn EJ, Savage NS, Sherwood DR - J. Cell Biol. (2014)

A model for UNC-40 (DCC)–mediated polarization toward UNC-6 (netrin). (A) In the absence of UNC-6, UNC-40 (DCC) undergoes oscillations in clustering (polarization). Positive feedback and competition mediates growth and dominance of a single UNC-40/F-actin cluster (middle). Cluster growth then leads to a delayed form of negative feedback (right, black cross) that breaks apart the cluster. After dissipation of negative feedback, the cycle repeats. (B, left) UNC-6 (netrin) in contact with UNC-40 (DCC) at the cell surface counteracts negative feedback, orienting and stabilizing polarity. (middle) Loss of the initial source of netrin leads to breakdown of polarity via negative feedback. (middle, right) A new source of netrin rapidly reorients and stabilizes polarity in a different location by countering negative feedback.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4151141&req=5

fig9: A model for UNC-40 (DCC)–mediated polarization toward UNC-6 (netrin). (A) In the absence of UNC-6, UNC-40 (DCC) undergoes oscillations in clustering (polarization). Positive feedback and competition mediates growth and dominance of a single UNC-40/F-actin cluster (middle). Cluster growth then leads to a delayed form of negative feedback (right, black cross) that breaks apart the cluster. After dissipation of negative feedback, the cycle repeats. (B, left) UNC-6 (netrin) in contact with UNC-40 (DCC) at the cell surface counteracts negative feedback, orienting and stabilizing polarity. (middle) Loss of the initial source of netrin leads to breakdown of polarity via negative feedback. (middle, right) A new source of netrin rapidly reorients and stabilizes polarity in a different location by countering negative feedback.
Mentions: The mechanism by which the receptor UNC-40 (DCC) polarizes toward its ligand UNC-6 (netrin) to mediate diverse guidance functions is poorly understood. Using C. elegans AC invasion as a model for UNC-40/UNC-6 polarization, we have found that in the absence of UNC-6, UNC-40 is active, generates F-actin, and undergoes oscillatory clustering characterized by repeated cycles of cluster assembly and disassembly at different regions of the cell surface. We show that UNC-6 orients and stabilizes UNC-40 clustering, and that the protein MADD-2, a direct regulator of UNC-40, promotes UNC-40 clustering and the ability of UNC-40 to polarize toward UNC-6. Together, our data suggest that UNC-6 (netrin) directs polarized responses by stabilizing the localization of oscillatory clustering of the DCC receptor (Fig. 9).

Bottom Line: By performing live-cell imaging of the DCC orthologue UNC-40 during anchor cell invasion in Caenorhabditis elegans, we have found that UNC-40 clusters, recruits F-actin effectors, and generates F-actin in the absence of UNC-6 (netrin).Together, our data suggest that UNC-6 (netrin) directs polarized responses by stabilizing UNC-40 clustering.We propose that ligand-independent UNC-40 clustering provides a robust and adaptable mechanism to polarize toward netrin.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Duke University, Durham, NC 27708.

Show MeSH
Related in: MedlinePlus