Wnt signaling pathways meet Rho GTPases

Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Genes & development (Impact Factor: 10.8). 03/2009; 23(3):265-77. DOI: 10.1101/gad.1760809
Source: PubMed


Wnt ligands and their receptors orchestrate many essential cellular and physiological processes. During development they control differentiation, proliferation, migration, and patterning, while in the adult, they regulate tissue homeostasis, primarily through their effects on stem cell proliferation and differentiation. Underpinning these diverse biological activities is a complex set of intracellular signaling pathways that are still poorly understood. Rho GTPases have emerged as key mediators of Wnt signals, most notably in the noncanonical pathways that involve polarized cell shape changes and migrations, but also more recently in the canonical pathway leading to beta-catenin-dependent transcription. It appears that Rho GTPases integrate Wnt-induced signals spatially and temporally to promote morphological and transcriptional changes affecting cell behavior.

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Available from: Nicholas S Tolwinski, Oct 10, 2015
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    • "The results are consistent with an earlier report of disrupted apicobasal polarity in Prickle1 mutant embryonic epiblasts (Tao et al., 2009). Actin assembly is a downstream event of PCP, which involves small GTPases (Schlessinger et al., 2009). We found that, rather than apical enrichment, the actin distribution was shifted more laterally in the mutant ureteric buds (Fig. 6E). "
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    ABSTRACT: Planar cell polarity (PCP) signaling plays a critical role in tissue morphogenesis. In mammals, disruption of three of the six ‘‘core PCP’’ components results in polarity-dependent defects with rotated cochlear hair cell stereocilia and open neural tube. We recently demonstrated a role of Prickle1, a core PCP molecule in Drosophila, in mammalian neuronal development. To examine Prickle1function along a broader developmental window, we generated three mutant alleles in mice. We show that the complete loss of Prickle1 leads to systemic tissue outgrowth defects, aberrant cell organization and disruption of polarity machinery. Curiously, Prickle1 mutants recapitulate the characteristic features of human Robinow syndrome and phenocopy mouse mutants with Wnt5a or Ror2 gene defects, prompting us to explore an association of Prickle1 with the Wnt pathway. We show that Prickle1 is a proteasomal target of Wnt5a signaling and that Dvl2, a target of Wnt5a signaling, is misregulated in Prickle1 mutants. Our studies implicate Prickle1 as a key component of the Wnt-signaling pathway and suggest that Prickle1 mediates some of the WNT5A-associated genetic defects in Robinow syndrome
    Biology Open 09/2014; 3(9):861-870. DOI:10.1242/bio.20148375 · 2.42 Impact Factor
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    • "In this regard, canonical Wnt signaling has been shown to maintain hemocyte precursors both directly by preventing their differentiation, and indirectly by promoting proliferation and maintenance of cells in the hematopoietic microenvironment that maintain precursor stemness [43]; more prolonged precursor status would allow for increased rounds of replication and eventual increased hemocyte numbers. Noncanonical Wnt signaling also impacts the hemocyte population, as Rac1 overexpression, acting via bsk, was shown to increase the number of circulating hemocytes by mobilizing the sessile hemocyte population [44]; Rac1 also increases canonical Wnt signaling by promoting arm nuclear translocation, either directly or by activated bsk phosphorylation of arm [45]. Finally, Rac1 and Rho1 GTPases, which both help regulate shape and migration of Drosophila hemocytes [46], can reciprocally induce each other: Rac1 acting via bsk, and Rho1 acting via dia [47]. "
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    ABSTRACT: Adaptation to hypoxia, defined as a condition of inadequate oxygen supply, has enabled humans to successfully colonize high altitude regions. The mechanisms attempted by organisms to cope with short-term hypoxia include increased ATP production via anaerobic respiration and stabilization of Hypoxia Inducible Factor 1α (HIF-1α). However, less is known about the means through which populations adapt to chronic hypoxia during the process of development within a life time or over generations. Here we show that signaling via the highly conserved Wnt pathway impacts the ability of Drosophila melanogaster to complete its life cycle under hypoxia. We identify this pathway through analyses of genome sequencing and gene expression of a Drosophila melanogaster population adapted over >180 generations to tolerate a concentration of 3.5-4% O2 in air. We then show that genetic activation of the Wnt canonical pathway leads to increased rates of adult eclosion in low O2. Our results indicate that a previously unsuspected major developmental pathway, Wnt, plays a significant role in hypoxia tolerance.
    PLoS ONE 08/2014; 9(8):e103292. DOI:10.1371/journal.pone.0103292 · 3.23 Impact Factor
    • "Recently this pathway was expanded to include a Pbx-dependent regulatory element controlling Wnt9b- Wnt3, which regulates p63 and Irf6 and is required for midface morphogenesis (Ferretti et al., 2011). Rho is a downstream effector of Wnt signaling (Schlessinger et al., 2009), and we suggest that the Rho signaling implicated in craniofacial development is mediated in part through the IRF6 gene regulatory network via ARHGAP29 (Fig. 4). Most of the variants identified in ARHGAP29 were predicted to be damaging (including truncation variants) and suggest a loss-of-function paradigm. "
    34th Annual Meeting of the; 04/2014
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