Unfolded‐protein response‐associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract

Lyu, Lei; Whitcomb, Elizabeth A.; Jiang, Shiqin; Chang, Min-Lee; Gu, Yumei; Duncan, Melinda K.; Cvekl, Aleš; Wang, Wei Lin; Limi, Saima; Reneker, Lixing W.; Shang, Fu; Du, Linfang; Taylor, Allen

doi:10.1096/fj.15-278036

Cited by 30 publications

(33 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…p27 Kip1 and Cdk1 are important for the disassembly of nuclei envelope and lens DNA degradation (Chaffee et al, 2014; Lyu et al, 2016; Rowan et al, 2016). During fiber cells differentiation the levels of p27 Kip1 protein decreases and becomes undetectable prior to nuclear disassembly.…”

Section: Resultsmentioning

confidence: 99%

N-myc regulates growth and fiber cell differentiation in lens development

Cavalheiro¹,

Matos-Rodrigues²,

Zhao³

et al. 2017

Developmental Biology

Self Cite

View full text Add to dashboard Cite

Myc proto-oncogenes regulate diverse cellular processes during development, but their roles during morphogenesis of specific tissues are not fully understood. We found that c-myc regulates cell proliferation in mouse lens development and previous genome-wide studies suggested functional roles for N-myc in developing lens. Here, we examined the role of N-myc in mouse lens development. Genetic inactivation of N-myc in the surface ectoderm or lens vesicle impaired eye and lens growth, while "late" inactivation in lens fibers had no effect. Unexpectedly, defective growth of N-myc--deficient lenses was not associated with alterations in lens progenitor cell proliferation or survival. Notably, N-myc-deficient lens exhibited a delay in degradation of DNA in terminally differentiating lens fiber cells. RNA-sequencing analysis of N-myc--deficient lenses identified a cohort of down-regulated genes associated with fiber cell differentiation that included DNaseIIβ. Further, an integrated analysis of differentially expressed genes in N-myc-deficient lens using normal lens expression patterns of iSyTE, N-myc-binding motif analysis and molecular interaction data from the String database led to the derivation of an N-myc-based gene regulatory network in the lens. Finally, analysis of N-myc and c-myc double-deficient lens demonstrated that these Myc genes cooperate to drive lens growth prior to lens vesicle stage. Together, these findings provide evidence for exclusive and cooperative functions of Myc transcription factors in mouse lens development and identify novel mechanisms by which N-myc regulates cell differentiation during eye morphogenesis.

show abstract

Section: Resultsmentioning

confidence: 99%

N-myc regulates growth and fiber cell differentiation in lens development

Cavalheiro¹,

Matos-Rodrigues²,

Zhao³

et al. 2017

Developmental Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Three of these models (collagen IV mutant, DN-FGFR, and dnNCOA6) elicit an unfolded protein response (Lyu et al, 2016). We also generated mouse models in which the ubiquitin pathway was perturbed by expression of the ubiquitin variant K6W-Ub (which has lysine 6 replaced by tryptophan).…”

Section: Relationship Between Mitosis and Lfcdmentioning

confidence: 99%

“…Common to each of these models is the activation of endoplasmic reticulum stress due to expression of the transgenes leading to an unfolded protein response (UPR), and associated stabilization of BiP (Fig. 4A)(Lyu et al, 2016). In comparison, expression of K6W-Ub does not show a UPR.…”

Section: Integrated Control Of Cdk1 Activity Via P27 – Role Of Unfmentioning

confidence: 99%

See 1 more Smart Citation

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

Rowan

Chang

Reznikov

et al. 2017

Experimental Eye Research

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…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). For example, a recent study has revealed a novel role of p27 Kip1 , upstream of Cdk1, in lens fiber cell denucleation (Lyu et al, 2016).…”

Section: Kip2mentioning

confidence: 99%

Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation

Limi

McGreal

et al. 2016

Development

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Unfolded‐protein response‐associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract

Cited by 30 publications

References 61 publications

N-myc regulates growth and fiber cell differentiation in lens development

N-myc regulates growth and fiber cell differentiation in lens development

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

Contact Info

Product

Resources

About