Activated Ras induces lens epithelial cell hyperplasia but not premature differentiation

Reneker, Lixing W.; Xie, Leike; Xu, Lan; Govindarajan, Venkatesh; Overbeek, Paul A.

doi:10.1387/ijdb.041889lr

Cited by 12 publications

(12 citation statements)

References 46 publications

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“…In lens, Reneker et al (2004) demonstrated that N-Ras is expressed in lenses as nearly undetectable in 21 day-old mouse lenses, which agrees with the present data demonstrating letÀ7a expression in 4 week-old mouse lenses.…”

Section: Discussionsupporting

confidence: 93%

miRNA and Dicer in the mammalian lens: expression of brain-specific miRNAs in the lens

Frederikse

Donnelly

Partyka

2006

Histochem Cell Biol

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Micro RNAs (miRNAs) are approximately 22 nucleotide molecules that regulate gene expression post-transcriptionally and govern a wide range of physiological and developmental processes. Evidence now indicates that miRNAs can also coordinately down-regulate transcript levels for very large groups of genes in a tissue-specific manner, in addition to their ability to suppress protein translation. Here, we examine expression of specific miRNAs and Dicer ribonuclease that is required for miRNA biogenesis in mouse and rat lenses. Northern blot analysis demonstrated lens expression of brain-specific miR-124 and miR-7 in lenses, as well as miR-125b and let-7a. In addition, we provide evidence that muscle specific miR-1 is not present in lens. We detected Dicer transcripts in 21 day, 6 week, and 1 year mouse lenses and 15 day rat lens, and detected Dicer protein in adult lens protein samples. Immunohistochemical examination of late embryonic, post-natal, and adult rat lens sections identified expression of Dicer in differentiating fiber cells that undergo pronounced cell elongation in the lens interior and anterior epithelial cells. The present study provides evidence that miRNAs, which include brain-specific forms, and Dicer are expressed in mammalian lenses, indicating that fundamental aspects of miRNA biology are utilized by the lens during late embryonic and post-natal development and in adult lenses.

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Section: Discussionsupporting

confidence: 93%

miRNA and Dicer in the mammalian lens: expression of brain-specific miRNAs in the lens

Frederikse

Donnelly

Partyka

2006

Histochem Cell Biol

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“…Despite this, Erk1/2 phosphorylation alone fails to induce a fiber cell differentiation response in explants (Wang et al, 2009). Also, transgenic mice expressing a constitutively active form of Ras in the lens exhibit increased Erk phosphorylation in the lens epithelium without the expression of either filensin (Bfsp1 -Mouse Genome Informatics) or -crystallins (Burgess et al, 2010;Reneker et al, 2004b), again demonstrating the insufficiency of Erk activation alone to induce a robust fiber differentiation response.…”

Section: F/2fmentioning

confidence: 99%

Frs2α enhances fibroblast growth factor-mediated survival and differentiation in lens development

et al. 2012

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SUMMARYMost growth factor receptor tyrosine kinases (RTKs) signal through similar intracellular pathways, but they often have divergent biological effects. Therefore, elucidating the mechanism of channeling the intracellular effect of RTK stimulation to facilitate specific biological responses represents a fundamental biological challenge. Lens epithelial cells express numerous RTKs with the ability to initiate the phosphorylation (activation) of Erk1/2 and PI3-K/Akt signaling. However, only Fgfr stimulation leads to lens fiber cell differentiation in the developing mammalian embryo. Additionally, within the lens, only Fgfrs activate the signal transduction molecule Frs2. Loss of Frs2 in the lens significantly increases apoptosis and decreases phosphorylation of both Erk1/2 and Akt. Also, Frs2 deficiency decreases the expression of several proteins characteristic of lens fiber cell differentiation, including Prox1, p57 KIP2 , aquaporin 0 and -crystallins. Although not normally expressed in the lens, the RTK TrkC phosphorylates Frs2 in response to binding the ligand NT3. Transgenic lens epithelial cells expressing both TrkC and NT3 exhibit several features characteristic of lens fiber cells. These include elongation, increased Erk1/2 and Akt phosphorylation, and the expression of -crystallins. All these characteristics of NT3-TrkC transgenic lens epithelial cells depend on Frs2. Therefore, tyrosine phosphorylation of Frs2 mediates Fgfr-dependent lens cell survival and provides a mechanistic basis for the unique fiber-differentiating capacity of Fgfs on mammalian lens epithelial cells.

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“…Previous studies in transgenic and knockout mouse models demonstrated that FGF-Ras signaling is essential for cell proliferation, differentiation and survival during lens development (Burgess et al, 2010;Garcia et al, 2005;Govindarajan and Overbeek, 2001;Pan et al, 2010;Qu et al, 2011;Reneker et al, 2004;Xie et al, 2006;Zhao et al, 2008). Abolishing MAPK activity with the MAPKK (or MEK) inhibitor U0126 blocks the FGF-induced cell proliferation and elongation response in rat lens explants (Lovicu and McAvoy, 2001).…”

Section: Introductionmentioning

confidence: 99%

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

2013

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SUMMARYThe mitogen-activated protein kinases (MAPKs; also known as ERKs) are key intracellular signaling molecules that are ubiquitously expressed in tissues and were assumed to be functionally equivalent. Here, we use the mouse lens as a model system to investigate whether MAPK1 plays a specific role during development. MAPK3 is known to be dispensable for lens development. We demonstrate that, although MAPK1 is uniformly expressed in the lens epithelium, its deletion significantly reduces cell proliferation in the peripheral region, an area referred to as the lens germinative zone in which most active cell division occurs during normal lens development. By contrast, cell proliferation in the central region is minimally affected by MAPK1 deletion. Cell cycle regulators, including cyclin D1 and survivin, are downregulated in the germinative zone of the MAPK1-deficient lens. Interestingly, loss of MAPK1 subsequently induces upregulation of phosphorylated MAPK3 (pMAPK3) levels in the lens epithelium; however, this increase in pMAPK3 is not sufficient to restore cell proliferation in the germinative zone. Additionally, MAPK1 plays an essential role in epithelial cell survival but is dispensable for fiber cell differentiation during lens development. Our data indicate that MAPK1/3 control cell proliferation in the lens epithelium in a spatially defined manner; MAPK1 plays a unique role in establishing the highly mitotic zone in the peripheral region, whereas the two MAPKs share a redundant role in controlling cell proliferation in the central region of the lens epithelium.

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Activated Ras induces lens epithelial cell hyperplasia but not premature differentiation

Cited by 12 publications

References 46 publications

miRNA and Dicer in the mammalian lens: expression of brain-specific miRNAs in the lens

miRNA and Dicer in the mammalian lens: expression of brain-specific miRNAs in the lens

Frs2α enhances fibroblast growth factor-mediated survival and differentiation in lens development

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

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