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The Wnt Frizzled Receptor MOM-5 Regulates the UNC-5 Netrin Receptor through Small GTPase-Dependent Signaling to Determine the Polarity of Migrating Cells.

Levy-Strumpf N, Krizus M, Zheng H, Brown L, Culotti JG - PLoS Genet. (2015)

Bottom Line: Using a genetic approach combined with temporal gene expression analysis, we found a regulatory link between the Wnt receptor MOM-5/Frizzled and the UNC-6/Netrin receptor UNC-5.We provide further evidence that small GTPases mediate MOM-5's regulation of unc-5 such that one outcome of impaired function of small GTPases like CED-10/Rac and MIG-2/RhoG is an increase in unc-5 function.The work presented here demonstrates the existence of cross talk between components of the Netrin and Wnt signaling pathways and provides further insights into the way guidance signaling mechanisms are integrated to orchestrate directed cell migration.

View Article: PubMed Central - PubMed

Affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.

ABSTRACT
Wnt and Netrin signaling regulate diverse essential functions. Using a genetic approach combined with temporal gene expression analysis, we found a regulatory link between the Wnt receptor MOM-5/Frizzled and the UNC-6/Netrin receptor UNC-5. These two receptors play key roles in guiding cell and axon migrations, including the migration of the C. elegans Distal Tip Cells (DTCs). DTCs migrate post-embryonically in three sequential phases: in the first phase along the Antero-Posterior (A/P) axis, in the second, along the Dorso-Ventral (D/V) axis, and in the third, along the A/P axis. Loss of MOM-5/Frizzled function causes third phase A/P polarity reversals of the migrating DTCs. We show that an over-expression of UNC-5 causes similar DTC A/P polarity reversals and that unc-5 deficits markedly suppress the A/P polarity reversals caused by mutations in mom-5/frizzled. This implicates MOM-5/Frizzled as a negative regulator of unc-5. We provide further evidence that small GTPases mediate MOM-5's regulation of unc-5 such that one outcome of impaired function of small GTPases like CED-10/Rac and MIG-2/RhoG is an increase in unc-5 function. The work presented here demonstrates the existence of cross talk between components of the Netrin and Wnt signaling pathways and provides further insights into the way guidance signaling mechanisms are integrated to orchestrate directed cell migration.

No MeSH data available.


Related in: MedlinePlus

Over-expression of the UNC-6/Netrin receptor UNC-5 causes DTC phase 3 A/P polarity reversals.DIC images of posterior gonad arms in L4 stage hermaphrodites overlaid with florescence images of GFP labeled DTCs. A DTC is located at the tip of each gonad arm. The migratory route taken by the DTC is depicted (white arrows). In all panels anterior is left and dorsal is up. (A) In the wild type, anterior and posterior U-shaped gonad arms are formed by 3 sequential migratory phases (labeled 1, 2, 3 accordingly) of the DTCs. Only the posterior gonad arm and DTC (visualized by the gly-18p::gfp reporter) are shown. (B) In evIs129[emb-9p::unc-5(+); emb-9p::gfp] animals the anterior or posterior (shown) DTC or both frequently migrates precociously towards the dorsal side. The first migratory phase is then completed on the dorsal muscle band and with normal timing the third migratory phase is initiated, reorienting the DTC back to the mid-body (left edge of photo). Dashed line represents the gonad segment formed in phase 1 that overlaps the segment formed in phase 3. (C) In evIs129 animals, in addition to the precocious migration of the DTC towards the dorsal side, the anterior or posterior DTC (marked by the emb-9p::gfp reporter) or both frequently exhibits an A/P polarity reversal that fails to reorient back to the mid-body.
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pgen.1005446.g001: Over-expression of the UNC-6/Netrin receptor UNC-5 causes DTC phase 3 A/P polarity reversals.DIC images of posterior gonad arms in L4 stage hermaphrodites overlaid with florescence images of GFP labeled DTCs. A DTC is located at the tip of each gonad arm. The migratory route taken by the DTC is depicted (white arrows). In all panels anterior is left and dorsal is up. (A) In the wild type, anterior and posterior U-shaped gonad arms are formed by 3 sequential migratory phases (labeled 1, 2, 3 accordingly) of the DTCs. Only the posterior gonad arm and DTC (visualized by the gly-18p::gfp reporter) are shown. (B) In evIs129[emb-9p::unc-5(+); emb-9p::gfp] animals the anterior or posterior (shown) DTC or both frequently migrates precociously towards the dorsal side. The first migratory phase is then completed on the dorsal muscle band and with normal timing the third migratory phase is initiated, reorienting the DTC back to the mid-body (left edge of photo). Dashed line represents the gonad segment formed in phase 1 that overlaps the segment formed in phase 3. (C) In evIs129 animals, in addition to the precocious migration of the DTC towards the dorsal side, the anterior or posterior DTC (marked by the emb-9p::gfp reporter) or both frequently exhibits an A/P polarity reversal that fails to reorient back to the mid-body.

Mentions: Cell migrations play a central role in both development and pathogenesis. However, the mechanisms underlying guided cell migration, and in particular the means by which extracellular information is integrated within the cell, are poorly understood. The C. elegans Distal Tip Cells (DTCs) provide an excellent model system to study various regulatory aspects of cell migration. In the hermaphrodite, a DTC is found at the extending tip of each of two elongating hermaphrodite gonad arms. These cells are born post-embryonically in the ventral mid-body and migrate along a stereotyped path involving 3 stages of polarized movements along A/P and D/V axes. In phase 1 the DTCs migrate away from each other along the A/P axis. In phase 2 the DTCs turn 90° and migrate along the D/V axis from the ventral to dorsal body wall muscles. In phase 3, the DTCs again turn 90° and migrate along the A/P axis back to the dorsal mid-body. This migration path determines the U shape of the two symmetrical gonad arms in wild-type animals (Fig 1A). Thus, by monitoring DTC movements in real time or gonad shapes in developed wild type and mutant hermaphrodites, insights may be gained into the regulation of sustained polarized migration over a single axis or transitions from one axis to another, which require the coordinated output of multiple guidance signaling pathways.


The Wnt Frizzled Receptor MOM-5 Regulates the UNC-5 Netrin Receptor through Small GTPase-Dependent Signaling to Determine the Polarity of Migrating Cells.

Levy-Strumpf N, Krizus M, Zheng H, Brown L, Culotti JG - PLoS Genet. (2015)

Over-expression of the UNC-6/Netrin receptor UNC-5 causes DTC phase 3 A/P polarity reversals.DIC images of posterior gonad arms in L4 stage hermaphrodites overlaid with florescence images of GFP labeled DTCs. A DTC is located at the tip of each gonad arm. The migratory route taken by the DTC is depicted (white arrows). In all panels anterior is left and dorsal is up. (A) In the wild type, anterior and posterior U-shaped gonad arms are formed by 3 sequential migratory phases (labeled 1, 2, 3 accordingly) of the DTCs. Only the posterior gonad arm and DTC (visualized by the gly-18p::gfp reporter) are shown. (B) In evIs129[emb-9p::unc-5(+); emb-9p::gfp] animals the anterior or posterior (shown) DTC or both frequently migrates precociously towards the dorsal side. The first migratory phase is then completed on the dorsal muscle band and with normal timing the third migratory phase is initiated, reorienting the DTC back to the mid-body (left edge of photo). Dashed line represents the gonad segment formed in phase 1 that overlaps the segment formed in phase 3. (C) In evIs129 animals, in addition to the precocious migration of the DTC towards the dorsal side, the anterior or posterior DTC (marked by the emb-9p::gfp reporter) or both frequently exhibits an A/P polarity reversal that fails to reorient back to the mid-body.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4546399&req=5

pgen.1005446.g001: Over-expression of the UNC-6/Netrin receptor UNC-5 causes DTC phase 3 A/P polarity reversals.DIC images of posterior gonad arms in L4 stage hermaphrodites overlaid with florescence images of GFP labeled DTCs. A DTC is located at the tip of each gonad arm. The migratory route taken by the DTC is depicted (white arrows). In all panels anterior is left and dorsal is up. (A) In the wild type, anterior and posterior U-shaped gonad arms are formed by 3 sequential migratory phases (labeled 1, 2, 3 accordingly) of the DTCs. Only the posterior gonad arm and DTC (visualized by the gly-18p::gfp reporter) are shown. (B) In evIs129[emb-9p::unc-5(+); emb-9p::gfp] animals the anterior or posterior (shown) DTC or both frequently migrates precociously towards the dorsal side. The first migratory phase is then completed on the dorsal muscle band and with normal timing the third migratory phase is initiated, reorienting the DTC back to the mid-body (left edge of photo). Dashed line represents the gonad segment formed in phase 1 that overlaps the segment formed in phase 3. (C) In evIs129 animals, in addition to the precocious migration of the DTC towards the dorsal side, the anterior or posterior DTC (marked by the emb-9p::gfp reporter) or both frequently exhibits an A/P polarity reversal that fails to reorient back to the mid-body.
Mentions: Cell migrations play a central role in both development and pathogenesis. However, the mechanisms underlying guided cell migration, and in particular the means by which extracellular information is integrated within the cell, are poorly understood. The C. elegans Distal Tip Cells (DTCs) provide an excellent model system to study various regulatory aspects of cell migration. In the hermaphrodite, a DTC is found at the extending tip of each of two elongating hermaphrodite gonad arms. These cells are born post-embryonically in the ventral mid-body and migrate along a stereotyped path involving 3 stages of polarized movements along A/P and D/V axes. In phase 1 the DTCs migrate away from each other along the A/P axis. In phase 2 the DTCs turn 90° and migrate along the D/V axis from the ventral to dorsal body wall muscles. In phase 3, the DTCs again turn 90° and migrate along the A/P axis back to the dorsal mid-body. This migration path determines the U shape of the two symmetrical gonad arms in wild-type animals (Fig 1A). Thus, by monitoring DTC movements in real time or gonad shapes in developed wild type and mutant hermaphrodites, insights may be gained into the regulation of sustained polarized migration over a single axis or transitions from one axis to another, which require the coordinated output of multiple guidance signaling pathways.

Bottom Line: Using a genetic approach combined with temporal gene expression analysis, we found a regulatory link between the Wnt receptor MOM-5/Frizzled and the UNC-6/Netrin receptor UNC-5.We provide further evidence that small GTPases mediate MOM-5's regulation of unc-5 such that one outcome of impaired function of small GTPases like CED-10/Rac and MIG-2/RhoG is an increase in unc-5 function.The work presented here demonstrates the existence of cross talk between components of the Netrin and Wnt signaling pathways and provides further insights into the way guidance signaling mechanisms are integrated to orchestrate directed cell migration.

View Article: PubMed Central - PubMed

Affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.

ABSTRACT
Wnt and Netrin signaling regulate diverse essential functions. Using a genetic approach combined with temporal gene expression analysis, we found a regulatory link between the Wnt receptor MOM-5/Frizzled and the UNC-6/Netrin receptor UNC-5. These two receptors play key roles in guiding cell and axon migrations, including the migration of the C. elegans Distal Tip Cells (DTCs). DTCs migrate post-embryonically in three sequential phases: in the first phase along the Antero-Posterior (A/P) axis, in the second, along the Dorso-Ventral (D/V) axis, and in the third, along the A/P axis. Loss of MOM-5/Frizzled function causes third phase A/P polarity reversals of the migrating DTCs. We show that an over-expression of UNC-5 causes similar DTC A/P polarity reversals and that unc-5 deficits markedly suppress the A/P polarity reversals caused by mutations in mom-5/frizzled. This implicates MOM-5/Frizzled as a negative regulator of unc-5. We provide further evidence that small GTPases mediate MOM-5's regulation of unc-5 such that one outcome of impaired function of small GTPases like CED-10/Rac and MIG-2/RhoG is an increase in unc-5 function. The work presented here demonstrates the existence of cross talk between components of the Netrin and Wnt signaling pathways and provides further insights into the way guidance signaling mechanisms are integrated to orchestrate directed cell migration.

No MeSH data available.


Related in: MedlinePlus