Nuclear removal during terminal lens fiber cell differentiation requires CDK1 activity: appropriating mitosis-related nuclear disassembly

Chaffee, Blake R.; Shang, Fu; Chang, Min-Lee; Clement, Tracy M.; Eddy, Edward M.; Wagner, Brad D.; Nakahara, Masaki; Nagata, Shinji; Robinson, Michael L.; Taylor, Allen

doi:10.1242/dev.106005

Cited by 55 publications

(62 citation statements)

References 47 publications

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“…We found that Cdk1 is nuclear and cytoplasmic in the bow region, but gradually becomes more nuclear toward the presumptive organelle free zone toward the center of the lens (Fig. 2A)(Chaffee et al, 2014). Cdk1 becomes activated through dephosphorylation by members of the Cdc25 phosphatase proteins.…”

Section: Relationship Between Mitosis and Lfcdmentioning

confidence: 91%

Disassembly of the lens fiber cell nucleus to create a clear lens: The p27 descent

Rowan

Chang

Reznikov

et al. 2017

Experimental Eye Research

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The eye lens is unique among tissues: it is transparent, does not form tumors, and the majority of its cells degrade their organelles, including their cell nuclei. A mystery for over a century, there has been considerable recent progress in elucidating mechanisms of lens fiber cell denucleation (LFCD). In contrast to the disassembly and reassembly of the cell nucleus during mitosis, LFCD is a unidirectional process that culminates in destruction of the fiber cell nucleus. Whereas p27Kip1, the cyclin-dependent kinase inhibitor, is upregulated during formation of LFC in the outermost cortex, in the inner cortex, in the nascent organelle free zone, p27Kip1 is degraded, markedly activating cyclin-dependent kinase 1 (Cdk1). This process results in phosphorylation of nuclear Lamins, dissociation of the nuclear membrane, and entry of lysosomes that liberate DNaseIIβ (DLAD) to cleave chromatin. Multiple cellular pathways, including the ubiquitin proteasome system and the unfolded protein response, converge on post-translational regulation of p27Kip1. Mutations that impair these pathways are associated with congenital cataracts and loss of LFCD. These findings highlight new regulatory nodes in the lens and suggest that we are close to understanding this fascinating terminal differentiation process. Such knowledge may offer a new means to confront proliferative diseases including cancer.

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Section: Relationship Between Mitosis and Lfcdmentioning

confidence: 91%

Disassembly of the lens fiber cell nucleus to create a clear lens: The p27 descent

Rowan

Chang

Reznikov

et al. 2017

Experimental Eye Research

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“…The reduction in phosphorylated LC3b proteins supports this possibility. In addition, lamin B phosphorylation mediated by Cdk1, a process that occurs during normal mitosis, is required for denucleation (Caceres et al, 2010;Chaffee et al, 2014). Further experiments are required to probe signaling upstream of JNK/mTOR, the phosphorylation of lamin B by Cdk1, and yet to be identified steps in the cascade of cellular and molecular events leading to nuclear degradation in lens fibers (Morishita and Mizushima, 2016).…”

Section: Kip2mentioning

confidence: 99%

Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation

Limi

McGreal

et al. 2016

Development

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Ocular lens morphogenesis is a model for investigating mechanisms of cellular differentiation, spatial and temporal gene expression control, and chromatin regulation. Brg1 (Smarca4) and Snf2h (Smarca5) are catalytic subunits of distinct ATP-dependent chromatin remodeling complexes implicated in transcriptional regulation. Previous studies have shown that Brg1 regulates both lens fiber cell differentiation and organized degradation of their nuclei (denucleation). Here, we employed a conditional Snf2h flox mouse model to probe the cellular and molecular mechanisms of lens formation. Depletion of Snf2h induces premature and expanded differentiation of lens precursor cells forming the lens vesicle, implicating Snf2h as a key regulator of lens vesicle polarity through spatial control of Prox1, Jag1, p27Kip1 (Cdkn1b) and p57Kip2 (Cdkn1c) gene expression. The abnormal Snf2h −/− fiber cells also retain their nuclei. RNA profiling of Snf2h −/− and Brg1 −/− eyes revealed differences in multiple transcripts, including prominent downregulation of those encoding Hsf4 and DNase IIβ, which are implicated in the denucleation process. In summary, our data suggest that Snf2h is essential for the establishment of lens vesicle polarity, partitioning of prospective lens epithelial and fiber cell compartments, lens fiber cell differentiation, and lens fiber cell nuclear degradation.

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“…Between E16 and E18, central lens fiber cells initiate the removal of cell nuclei, a process that requires the nuclease DnaseIIβ (Bassnett, 1997, 2009; Chaffee et al, 2014; Nakahara et al, 2007). Both Fgfr2 Δ/Δ and (Pten/R2) Δ/Δ lenses retained nuclei in central lens fiber cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

FGFR and PTEN signaling interact during lens development to regulate cell survival

Chaffee

Hoang

Leonard

et al. 2016

Developmental Biology

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Lens epithelial cells express many receptor tyrosine kinases (RTKs) that stimulate PI3K-AKT and RAS-RAF-MEK-ERK intracellular signaling pathways. These pathways ultimately activate the phosphorylation of key cellular transcription factors and other proteins that control proliferation, survival, metabolism, and differentiation in virtually all cells. Among RTKs in the lens, only stimulation of fibroblast growth factor receptors (FGFRs) elicits a lens epithelial cell to fiber cell differentiation response in mammals. Moreover, although the lens expresses three different Fgfr genes, the isolated removal of Fgfr2 at the lens placode stage inhibits both lens cell survival and fiber cell differentiation. Phosphatase and tensin homolog (PTEN), commonly known as a tumor suppressor, inhibits ERK and AKT activation and initiates both apoptotic pathways, and cell cycle arrest. Here, we show that the combined deletion of Fgfr2 and Pten rescues the cell death phenotype associated with Fgfr2 loss alone. Additionally, Pten removal increased AKT and ERK activation, above the levels of controls, in the presence or absence of Fgfr2. However, isolated deletion of Pten failed to stimulate ectopic fiber cell differentiation, and the combined deletion of Pten and Fgfr2 failed to restore differentiation-specific Aquaporin0 and DnaseIIβ expression in the lens fiber cells.

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Nuclear removal during terminal lens fiber cell differentiation requires CDK1 activity: appropriating mitosis-related nuclear disassembly

Cited by 55 publications

References 47 publications

Disassembly of the lens fiber cell nucleus to create a clear lens: The p27 descent

Disassembly of the lens fiber cell nucleus to create a clear lens: The p27 descent

Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation

FGFR and PTEN signaling interact during lens development to regulate cell survival

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