Functions of the intermediate filament cytoskeleton in the eye lens

Song, S.; Landsbury, Andrew; Dahm, Ralf; Liu, Yizhi; Zhang, Qingjiong; Quinlan, Roy A.

doi:10.1172/jci38277

Cited by 157 publications

(116 citation statements)

References 112 publications

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“…S7.3). Interestingly, the pseudogenization of BFSP2 and GUCA1C have been reported in mice with reduced vision, supporting the hypothesis that the two genes are likely associated with the poor vision of pangolins (Imanishi et al 2002;Sandilands et al 2004;Song et al 2009).…”

Section: Pangolin-specific Phenotypessupporting

confidence: 56%

Pangolin genomes and the evolution of mammalian scales and immunity

et al. 2016

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Pangolins, unique mammals with scales over most of their body, no teeth, poor vision, and an acute olfactory system, comprise the only placental order (Pholidota) without a whole-genome map. To investigate pangolin biology and evolution, we developed genome assemblies of the Malayan (Manis javanica) and Chinese (M. pentadactyla) pangolins. Strikingly, we found that interferon epsilon (IFNE), exclusively expressed in epithelial cells and important in skin and mucosal immunity, is pseudogenized in all African and Asian pangolin species that we examined, perhaps impacting resistance to infection. We propose that scale development was an innovation that provided protection against injuries or stress and reduced pangolin vulnerability to infection. Further evidence of specialized adaptations was evident from positively selected genes involving immunity-related pathways, inflammation, energy storage and metabolism, muscular and nervous systems, and scale/hair development. Olfactory receptor gene families are significantly expanded in pangolins, reflecting their well-developed olfaction system. This study provides insights into mammalian adaptation and functional diversification, new research tools and questions, and perhaps a new natural IFNE-deficient animal model for studying mammalian immunity.

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Section: Pangolin-specific Phenotypessupporting

confidence: 56%

Pangolin genomes and the evolution of mammalian scales and immunity

et al. 2016

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“…However, IFs contain numerous phosphorylation sites, and the function of their in vivo phosphorylation and their hierarchal regulation (including dephosphorylation) is poorly understood. In addition, relatively few IF-associated proteins have been identified, but the list of these proteins is ever growing (4,33), and there are several examples of IF-pathies that are caused by mutations in genes encoding either IF proteins or their associated proteins (19,20).…”

Section: Numerous Opportunities and Challenges In The If Fieldmentioning

confidence: 99%

“IF-pathies”: a broad spectrum of intermediate filament–associated diseases

2009

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Intermediate filaments (IFs) are encoded by the largest gene family among the three major cytoskeletal protein groups. Unique IF compliments are expressed in selective cell types, and this expression is reflected in their involvement, upon mutation, as a cause of or predisposition to more than 80 human tissue-specific diseases. This Review Series covers diseases and functional and structural aspects pertaining to IFs and highlights the molecular and functional consequences of IF-associated diseases (IF-pathies). Exciting challenges and opportunities face the IF field, including developing both a better understanding of the pathogenesis of IF-pathies and targeted therapeutic approaches. Intermediate filamentsIntermediate filaments (IFs), microfilaments (MFs), and microtubules (MTs) are the major fibrillar cytoplasmic elements that make up what is referred to as the cytoskeleton. IFs consist of a large protein family that includes 73 unique gene products, which places the genes encoding them among the 100 largest gene families in humans (1). The IF proteins are grouped into six types (types I-VI): those in types I-IV are found in the cytoplasm, the type V IF proteins are found in the nucleus, and those classified as type VI are found exclusively in the lens (Table 1). Several features distinguish IFs (2-4) from MFs and MTs, including IF structural diversity, tissue- and cell-selective expression, unique subcellular compartment distribution (lamins are found in the nucleus, whereas the remaining IFs are in the cytoplasm), relative insolubility, nucleotide-independent assembly, restricted expression to higher eukaryotes, and, most relevant, their involvement in more than 80 human diseases (Human Intermediate Filament Database, http://www.interfil.org/index.php) (5). Another distinguishing feature of IFs is their regulation (primarily but not exclusively) by phosphorylation, whereas MFs and MTs are regulated preferentially but not exclusively by their associated proteins and posttranslational modifications other than phosphorylation (6). Furthermore, IFs are characteristically resistant to breakage when mechanically stressed, whereas MFs and MTs are far less compliant (7).In addition to the unique and complex cell and tissue distribution of IFs (Figure 1), the expression of some IF proteins is highly regulated during development and cell differentiation and can be markedly induced in cells and tissues undergoing an injury response. For example, keratin 5 and 14 (K5/K14) are found in basal keratinocytes, whereas K1/K10 are found in the differentiating layers of suprabasal epidermis (8); K19 is found in fetal but not normal adult hepatocytes (9); K19/K20 (10) and K6/K16 (11) are highly induced in response to pancreatic acinar cell and skin injury, respectively; and glial fibrillary acidic protein (GFAP) is upregulated during reactive gliosis (12). The Review SeriesThe Review Series herein includes eight state-of-the-art treatises by leaders in the field. The first article, by John Eriksson, Robert Goldman, and colleagu...

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“…These are the principal cytoskeletal element of the eye lens and are essential in maintaining lens cell architecture and the lens optical properties (Song et al, 2009). …”

Section: Type Vi: the Lens If Proteins Filensin And Phakininmentioning

confidence: 99%

Insights into intermediate filament regulation from development to ageing

Hyder

Isoniemi

Torvaldson

et al. 2011

Journal of Cell Science

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SummaryIntermediate filament (IF) proteins comprise a large family with more than 70 members. Initially, IFs were assumed to provide only structural reinforcement for the cell. However, IFs are now known to be dynamic structures that are involved in a wide range of cellular processes during all stages of life, from development to ageing, and during homeostasis and stress. This Commentary discusses some lesser-known functional and regulatory aspects of IFs. We specifically address the emerging roles of nestin in myogenesis and cancer cell migration, and examine exciting evidence on the regulation of nestin and lamin A by the notch signalling pathway, which could have repercussions for our understanding of the roles of IF proteins in development and ageing. In addition, we discuss the modulation of the post-translational modifications of neuronally expressed IFs and their protein-protein interactions, as well as IF glycosylation, which not only has a role in stress and ageing, but might also regulate IFs during development. Although many of these recent findings are still preliminary, they nevertheless open new doors to explore the functionality of the IF family of proteins. Journal of Cell ScienceCdk5 is associated with nestin in myoblasts, neuronal precursor cells (Sahlgren et al., 2003) and human podocytes (Bertelli et al., 2007). Cdk5 phosphorylates nestin, and this phosphorylation regulates the organization of nestin filaments (Box 2) during myogenic differentiation (Sahlgren et al., 2003). Interestingly, the interaction between nestin and Cdk5 is not limited to a typical kinase-substrate relationship. In neuronal precursor cells, nestin forms a scaffold for Cdk5 and the Cdk5 activator p35, thereby sequestering them to the cytoplasm, which consequently inhibits the proapoptotic function of Cdk5 during oxidative stress (Sahlgren et al., 2006). In turn, it has recently been demonstrated that Cdk5 is targeted by protein kinase C- (PKC) during myogenesis (de Thonel et al., 2010). PKC is essential for proper myoblast differentiation. It targets Cdk5 by phosphorylating p35 at a site that triggers the activation of calpains, which then cleave p35 into p25. The cleavage of p35 into p25 creates a more stable protein fragment, and this fragment is capable of sustained Cdk5 activation, consequently promoting nestin reorganization (Fig. 1,. An earlier study, in cultured neurons, demonstrated that Cdk5 is also able to regulate p35 by phosphorylation, thereby protecting it from calpain-mediated cleavage (Kamei et al., 2007). Furthermore, a recent study has shown that nestin has the capacity to modulate Cdk5-mediated differentiation and terminal organization of muscle cells (Pallari et al., 2011) (Fig. 1, left-hand side). Taken together, these results suggest that a balance between Cdk5 and PKC is important for proper myogenic differentiation, as they show that disturbance of the PKC-Cdk5-nestin signalling pathway leads to nestin reorganization and impedes myoblast differentiation, implying that nestin also plays a k...

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Functions of the intermediate filament cytoskeleton in the eye lens

Cited by 157 publications

References 112 publications

Pangolin genomes and the evolution of mammalian scales and immunity

Pangolin genomes and the evolution of mammalian scales and immunity

“IF-pathies”: a broad spectrum of intermediate filament–associated diseases

Insights into intermediate filament regulation from development to ageing

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