MAPK1 is required for establishing the pattern of cell proliferation and for cell survival during lens development

Upadhya, Dinesh; Ogata, Masato; Reneker, Lixing W.

doi:10.1242/dev.081042

Cited by 53 publications

(58 citation statements)

References 54 publications

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“…Ras signaling is known to have multiple downstream effector pathways, including RAF-MEK-ERK, PI3K and RalGDS. Importantly, Upadhya and colleagues (Upadhya et al, 2013) recently showed that genetic deletion of Erk1 and Erk2 in the lens also caused significant reduction in cell proliferation and aberrant apoptosis, but unlike the eventual loss of lens structure in our Frs2a and Shp2 mutants, embryos lacking Erk1 and Erk2 appear to retain a rudimentary lens at E14.5 (Upadhya et al, 2013). Whether additional Ras downstream effector pathways complement ERK signaling in lens development will be an important topic for future study.…”

Section: Discussionmentioning

confidence: 77%

“…) lacking two tyrosine residues required for binding of Shp2 protein displays lens and retina developmental failure, whereas genetic ablation of the Ras signaling molecules Shp2, Nf1 and ERK disrupts lens development (Gotoh et al, 2004;Pan et al, 2010;Carbe and Zhang, 2011;Upadhya et al, 2013). However, it was recently reported that a lens-specific knockout of Frs2a results in a well-differentiated lens with only moderately reduced size (Madakashira et al, 2012).…”

Section: Fmentioning

confidence: 99%

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Frs2α and Shp2 signal independently of Gab to mediate FGF signaling in lens development

Li¹,

Tao²,

Cai³

et al. 2013

Journal of Cell Science

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Fibroblast growth factor (FGF) signaling requires a plethora of adaptor proteins to elicit downstream responses, but the functional significances of these docking proteins remain controversial. In this study, we used lens development as a model to investigate Frs2a and its structurally related scaffolding proteins, Gab1 and Gab2, in FGF signaling. We show that genetic ablation of Frs2a alone has a modest effect, but additional deletion of tyrosine phosphatase Shp2 causes a complete arrest of lens vesicle development. Biochemical evidence suggests that this Frs2a-Shp2 synergy reflects their epistatic relationship in the FGF signaling cascade, as opposed to compensatory or parallel functions of these two proteins. Genetic interaction experiments further demonstrate that direct binding of Shp2 to Frs2a is necessary for activation of ERK signaling, whereas constitutive activation of either Shp2 or Kras signaling can compensate for the absence of Frs2a in lens development. By contrast, knockout of Gab1 and Gab2 failed to disrupt FGF signaling in vitro and lens development in vivo. These results establish the Frs2a-Shp2 complex as the key mediator of FGF signaling in lens development.

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Section: Discussionmentioning

confidence: 77%

Section: Fmentioning

confidence: 99%

Frs2α and Shp2 signal independently of Gab to mediate FGF signaling in lens development

Li¹,

Tao²,

Cai³

et al. 2013

Journal of Cell Science

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“…The detailed procedures to obtain the embryos were described for the Erk2/Mapk1 model earlier (13). Lens fiber cell differentiation was analyzed in both E12.5 and E13.5 embryos.…”

Section: Methodsmentioning

confidence: 99%

“…9621), ␣B-crystallin (1:500, Enzo Life Science, ADI-SPA-223), ␤-and ␥-crystallin antibodies (1:100, 1:50, Santa Cruz 22745 and 22746, respectively), ERM (1:1000, Santa Cruz, sc-22807) diluted in PBS containing 1% BSA and 0.05% Triton-X100. Antibodies against ␣A-crystallin (1:500) were described elsewhere (13). After washing with PBS, the slides were incubated for 45 min with goat anti-rabbit IgG secondary antibodies conjugated with Alexa Fluor 488 or 568 (1:500, Invitrogen), and with DAPI (1:50000, Invitrogen).…”

Section: Erk2mentioning

confidence: 99%

Regulation of c-Maf and αA-Crystallin in Ocular Lens by Fibroblast Growth Factor Signaling

Xie

McGreal²,

Harris

et al. 2016

Journal of Biological Chemistry

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During embryonic development, the fibroblast growth factor (FGF) 3 signal transduction pathway regulates a range of cellular processes including cell proliferation, survival, migration, and differentiation (1). The mammalian FGF signaling is mediated by the interaction of specific secreted FGFs (i.e. FGF1 to FGF10) that work in conjunction with a specialized class of transmembrane receptor tyrosine kinases, the FGF receptors (FGFR1 to FGFR4). Formation of a complex between the dimeric FGFR and its FGF ligand dimer triggers a cascade of intracellular processes relayed by mitogen-activated kinases (MAPKs) such as Erk1 (official gene name: Mapk3) and Erk2 (Mapk1), PI-3/Akt kinase system, and other kinases. Upon entering the nucleus, Erk1/2 kinases elicit transcription of specific DNA-binding transcription factors and/or their post-translational modifications. While the majority of FGF signaling output includes activation of cell proliferation, survival, and motility, FGF signaling also regulates lens, myoblast, and osteogenic terminal differentiation (1, 2).The ocular lens has served as an advantageous model for studies of FGF signaling over many years (2). Primary rodent lens cell culture experiments showed that addition of a "high" concentration of bFGF/FGF2 (40 ng/ml) alone induced lens fiber cell terminal differentiation while "low" (0.15 ng/ml) and moderate (3 ng/ml) concentrations control cell survival and migration, respectively (3-5). FGF signaling is also modulated by the lens capsule, an extracellular matrix serving as an interface between the lens, aqueous and vitreous humor (6, 7). Subsequent genetic studies of FGF receptors (8, 9), components of the Frs2␣/Ras/MAPK signaling arm (10 -13), and the cooperating heparan sulfate biosynthesis pathway (14, 15) demonstrated in vivo roles of FGF signaling in mouse lens fiber cell survival and differentiation, and identified a set of lens regulatory genes, including c-Maf, Prox1, Etv1 (ER81), and Etv5 (ERM), whose expression was attenuated following genetic disruption of the FGF signaling pathway (9,14,15).Among these factors, Etv1 and Etv5 are well-established nuclear components of FGF signaling during neural development (16). The bZIP nuclear oncogene c-Maf encodes an important DNA-binding transcription factor that controls lens fiber cell differentiation through crystallin target genes (17). In addition to the lens, c-Maf regulates T-cell (18) and chondrocyte differentiation (19). Up-regulation of MAF was found in multiple myeloma cells and is a potential therapeutic target to treat this cancer (20). Therefore, a thorough understanding of c-Maf transcriptional control relates not only to the basic question of embryonic development but also for dysregulated gene expression during oncogenesis.

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“…Furthermore, cell division orientation is biased longitudinally in the anterior region and circumferentially in the peripheral region of lens epithelium, suggesting a spatial pattern of cell division orientation. Although the FGF-Ras-MAPK pathway is required for active cell proliferation in the germinative zone in mice (Upadhya et al, 2013), it is unclear how cell proliferation and cell division orientation are spatially regulated and how these spatial patterns influence cell movement.…”

Section: Introductionmentioning

confidence: 99%

Cell division and cadherin-mediated adhesion regulate lens epithelial cell movement in zebrafish

Mochizuki¹,

Luo²,

Tsai³

et al. 2017

Journal of Cell Science

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In vertebrates, lens epithelial cells cover the anterior half of the lens fiber core. During development, lens epithelial cells proliferate, move posteriorly and differentiate into lens fiber cells after passing through the equator. To elucidate the mechanisms underlying lens epithelial cell movement, we conducted time-lapse imaging of zebrafish lens epithelium. Lens epithelial cells do not intermingle but maintain their relative positions during development. Cell division induces epithelial rearrangement, which subsequently promotes cell movement towards the equator. These data suggest that cell division is the major driving force for cell movement. In zebrafish, E-cadherin is expressed in lens epithelium, whereas N-cadherin is required for lens fiber growth. E-cadherin reduced lens epithelial cell movement, whereas N-cadherin enhanced it. Laser ablation experiments revealed that lens epithelium is governed by pulling tension, which is modulated by these cadherins. Thus, cell division and cadherinmediated adhesion regulate lens epithelial cell movement via modulation of epithelial tension.

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MAPK1 is required for establishing the pattern of cell proliferation and for cell survival during lens development

Cited by 53 publications

References 54 publications

Frs2α and Shp2 signal independently of Gab to mediate FGF signaling in lens development

Frs2α and Shp2 signal independently of Gab to mediate FGF signaling in lens development

Regulation of c-Maf and αA-Crystallin in Ocular Lens by Fibroblast Growth Factor Signaling

Cell division and cadherin-mediated adhesion regulate lens epithelial cell movement in zebrafish

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