Multiple functions of the noncanonical Wnt pathway

Gómez-Orte, Eva; Sáenz-Narciso, Beatriz; Moreno, Sergio; Cabello, Juan

doi:10.1016/j.tig.2013.06.003

Cited by 129 publications

(115 citation statements)

References 71 publications

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“…Similar observations could be achieved when the Ishikawa cells were transfected with a dominant negative Rac1 (N17Rac1) 26 (Figure 5f). Because Rac1 is a known target of Wnt5a signaling 35,36 that has been shown to be essential for cell polarity induction and epithelial function in various organs including the uterus, 9,11,37 we also analyzed the consequence of Rac1 deficiency on uterine Wnt5a expression. As shown in Figure 5g, Wnt5a was comparably expressed in both Rac1 f/f and Rac1 d/d luminal epithelia.…”

Section: Resultsmentioning

confidence: 99%

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Wang

Cui

et al. 2015

Cell Death Differ

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Successful embryo implantation requires functional luminal epithelia to establish uterine receptivity and blastocyst-uterine adhesion. During the configuration of uterine receptivity from prereceptive phase, the luminal epithelium undergoes dynamic membrane reorganization and depolarization. This timely regulated epithelial membrane maturation and precisely maintained epithelial integrity are critical for embryo implantation in both humans and mice. However, it remained largely unexplored with respect to potential signaling cascades governing this functional epithelial transformation prior to implantation. Using multiple genetic and cellular approaches combined with uterine conditional Rac1 deletion mouse model, we demonstrated herein that Rac1, a small GTPase, is spatiotemporally expressed in the periimplantation uterus, and uterine depletion of Rac1 induces premature decrease of epithelial apical-basal polarity and defective junction remodeling, leading to disrupted uterine receptivity and implantation failure. Further investigations identified Pak1-ERM as a downstream signaling cascade upon Rac1 activation in the luminal epithelium necessary for uterine receptivity. In addition, we also demonstrated that Rac1 via P38 MAPK signaling ensures timely epithelial apoptotic death at postimplantation. Besides uncovering a potentially important molecule machinery governing uterine luminal integrity for embryo implantation, our finding has high clinical relevance, because Rac1 is essential for normal endometrial functions in women. The implantation of the blastocyst into the maternal uterus is a crucial step in establishing pregnancy and thus ensuring further embryonic development. 1-3 Similar to many developmental processes, implantation involves an intricate succession of molecular and cellular interactions which must be executed within an optimal time frame. During this period, the acquisition of blastocyst implantation competency is synchronized with the establishment of uterine receptivity. [4][5][6] On the basis of previous findings, uterine sensitivity to implantationcompetent blastocysts is classically divided into three stages: pre-receptive, receptive and refractory phases. 7 In mice, prior to day 4 of pregnancy, the uterus is conventionally considered as the pre-receptive phase. On day 4 and beyond, the uterus becomes fully receptive following the priming actions of ovarian progesterone and preimplantation estrogen; whereas by late day 5, the uterus becomes refractory to initiate the implantation. 2,4,8 Upon entering the receptive phase, uterine luminal epithelium undergoes dynamic transformation. For example, on day 4 morning in mice, luminal epithelial cells cease proliferation under the dominance of increasing levels of ovarian progesterone and preimplantation estrogen. Meanwhile, the epithelial cells undergo differentiation, accompanied with a dynamic junction complex remodeling and membrane maturation, leading to a decrease of epithelial polarity approaching implantation and a cell-shape transition from...

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Section: Resultsmentioning

confidence: 99%

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Wang

Cui

et al. 2015

Cell Death Differ

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“…2) regulate DVL and other intracellular proteins to activate the Planar Cell Polarity (PCP) pathway, the Wnt-Calcium (Ca 2+ ) pathway and other -catenin/TCF-independent events [18]. In the Wnt-PCP pathway, FZD receptors activate a signaling cascade that involves the small GTPases Rho and Rac and c-Jun N-terminal kinase (JNK), leading to changes in the cytoskeleton and activation of Activator Protein-1 (AP-1) family transcription factors [19]. Noncanonical Wnt stimuli induce association of DVL associated activator of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 morphogenesis (DAAM) proteins with FZD, DVL and GTP-bound Rho, which is then able to activate Rho-associated, coiled-coil containing protein kinase (ROCK) and even JNK.…”

Section: Noncanonical Wnt Signalingmentioning

confidence: 99%

“…Although JNK is generally associated with phosphorylation and activation of c-Jun, it phosphorylates many other proteins, including activating transcription factor 2 (ATF2) and cyclic AMP response element-binding protein (CREB), which heterodimerize with c-Jun and other AP-1 family members to alter gene expression [20]. This pathway regulates cell polarity in several morphogenetic processes in vertebrates, including gastrulation, neural tube closure and orientation of stereocilia in the inner ear [19]. Calcineurin, CNA; calmodulin kinase II, CAMKII; phospholipase C, PLC; adenylate cyclase, AC; mitogen-activated protein kinase kinase, MKK.…”

Section: Noncanonical Wnt Signalingmentioning

confidence: 99%

“…Similarly, ROR1 activates the same signaling cascade to increase CREB phosphorylation in human breast cancer cells [29]. FZDs have been found to activate a number of additional intracellular effectors, including adenylate cyclase (AC), protein kinase A (PKA) and CREB [19], p38 and ATF2 [20] and Fyn and STAT3 [21]. In addition, a new -catenin-independent aspect of Wnt signaling was recently reported in proliferating cells: Wnt signaling was found to peak at the G2/M phase of the cell cycle to produce so-called Wnt-dependent stabilization of proteins (Wnt/STOP) [30].…”

Section: Noncanonical Wnt Signalingmentioning

confidence: 99%

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Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

Bengoa-Vergniory

Kypta

2015

Cell. Mol. Life Sci.

135

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“…These mitotic spindle orientations are induced by cell signaling, from blastomeres derived from the posterior cell at the two‐cell stage embryo − termed P1 −, that triggers actin cytoskeletal reorganizations in the target cells. In C. elegans , these rearrangements are controlled by a polarized Wnt signaling 17 and are part of the process that diversify the fate of the daughter cells after division. Upon local activation of the MOM‐5/Frizzled receptor by a Wnt ligand, at the cellular membrane, the signal is transduced through a signaling cascade until it reaches β‐catenin.…”

Section: Rac/rho Small Gtpases Mediate Spindle Orientation and Cell Dmentioning

confidence: 99%

Control of developmental networks by Rac/Rho small GTPases: How cytoskeletal changes during embryogenesis are orchestrated

et al. 2016

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Small GTPases in the Rho family act as major nodes with functions beyond cytoskeletal rearrangements shaping the Caenorhabditis elegans embryo during development. These small GTPases are key signal transducers that integrate diverse developmental signals to produce a coordinated response in the cell. In C. elegans, the best studied members of these highly conserved Rho family small GTPases, RHO‐1/RhoA, CED‐10/Rac, and CDC‐42, are crucial in several cellular processes dealing with cytoskeletal reorganization. In this review, we update the functions described for the Rho family small GTPases in spindle orientation and cell division, engulfment, and cellular movements during C. elegans embryogenesis, focusing on the Rho subfamily Rac.Please also see the video abstract here

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Multiple functions of the noncanonical Wnt pathway

Cited by 129 publications

References 71 publications

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

Control of developmental networks by Rac/Rho small GTPases: How cytoskeletal changes during embryogenesis are orchestrated

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