Ankyrin-G regulated epithelial phenotype is required for mouse lens morphogenesis and growth

Rasiah, Pratheepa Kumari; Maddala, Rupalatha; Bennett, Vann; Rao, Ponugoti Vasantha

doi:10.1016/j.ydbio.2018.12.016

Cited by 6 publications

(7 citation statements)

References 43 publications

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“…Significantly, the drebrin cKO lens epithelium reveals abnormalities very similar to those we have previously observed in mouse models with impairments in molecular mechanisms regulating actin cytoskeletal dynamics in the lens. These include alterations in epithelial apical-basal height and sheet length, E-cadherin-based junctions, and induction of epithelial to mesenchymal transdifferentiation, 13,17 further confirming the importance of proteins including drebrin that regulate actin cytoskeletal organization and actin dynamics in maintaining the lens epithelial phenotype. What is surprising about drebrin is that unlike many other prominently expressed cytoskeletal and cytoskeleton interacting proteins in the lens, 1,5 even haploinsufficiency of the protein results in impairment of lens morphogenesis and growth, indicating an absolute requirement for normal levels of drebrin expression in lens development and growth.…”

Section: Discussionmentioning

confidence: 76%

“…5 These events include invagination of the lens placode, separation of LV from the surface ectoderm, epithelial morphogenesis, polarity, epithelial differentiation and elongation into fiber cells, fiber cell migration, maintenance of fiber cell hexagonal shape, membrane organization, and cell-cell adhesion. 5,[9][10][11][12][13][14][15][16][17] Further, it is also well recognized that actin cytoskeletal reorganization and assembly are involved in the etiology of secondary cataract, which is driven primarily by the trans differentiation of epithelial cells into mesenchymal cells. [18][19][20] Despite the recognition that the actin cytoskeleton plays a critical role in lens morphogenesis, growth, and architecture, our knowledge of actin-binding proteins that play a key role in regulating lens actin cytoskeletal organization and dynamics is very limited.…”

Section: Introductionmentioning

confidence: 99%

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Drebrin, an actin‐binding protein, is required for lens morphogenesis and growth

Karnam

Maddala

Stiber

et al. 2021

Developmental Dynamics

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Background: Lens morphogenesis, architecture, and clarity are known to be critically dependent on actin cytoskeleton organization and cell adhesive interactions. There is limited knowledge, however regarding the identity and role of key proteins regulating actin cytoskeletal organization in the lens. This study investigated the role of drebrin, a developmentally regulated actinbinding protein, in mouse lens development by generating and characterizing a conditional knockout (cKO) mouse model using the Cre-LoxP recombination approach. Results: Drebrin E, a splice variant of DBN1 is a predominant isoform expressed in the mouse lens and exhibits a maturation-dependent downregulation. Drebrin co-distributes with actin in both epithelium and fibers.Conditional deficiency (both haploinsufficiency and complete absence) of drebrin results in disrupted lens morphogenesis leading to cataract and microphthalmia. The drebrin cKO lens reveals a dramatic decrease in epithelial height and width, E-cadherin, and proliferation, and increased apoptotic cell death and expression of α-smooth muscle actin, together with severely impaired fiber cell organization, polarity, and cell-cell adhesion.Conclusions: This study demonstrates the requirement of drebrin in lens development and growth, with drebrin deficiency leading to impaired lens morphogenesis and microphthalmia.

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Drebrin, an actin‐binding protein, is required for lens morphogenesis and growth

Karnam

Maddala

Stiber

et al. 2021

Developmental Dynamics

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“…It is indispensable for microtubule activity to initiate and maintain the change in endothelial shape and dynamics of polarized cells induced by vascular endothelial growth factor (48). In addition, Ank3 was shown to play a vital role in cadherin membrane localization and endocytosis in epithelial cells using Ank3 conditional knockout mice (49). Cadherin-mediated cell adhesion and dynamics can affect cell migration as well as the regulation of angiogenesis by vascular endothelial growth factor and its signaling pathways (48).…”

Section: Discussionmentioning

confidence: 99%

A Rare Variant of ANK3 Is Associated With Intracranial Aneurysm

et al. 2021

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Intracranial aneurysm (IA) is a cerebrovascular disorder in which abnormal dilation of a blood vessel results from weakening of the blood vessel wall. The aneurysm may rupture, leading to subarachnoid hemorrhage with severe outcomes. This study was conducted to identify the genetic factors involved in the etiology of IA. Whole-exome sequencing was performed in three IA-aggregate families to identify candidate variants. Further association studies of candidate variants were performed among sporadic cases and controls. Bioinformatic analysis was used to predict the functions of candidate genes and variants. Twenty variants were identified after whole-exome sequencing, among which eight were selected for replicative association studies. ANK3 c.4403G>A (p.R1468H) was significantly associated with IA (odds ratio 4.77; 95% confidence interval 1.94–11.67; p-value = 0.00019). Amino acid R1468 in ANK3 was predicted to be located in the spectrin-binding domain of ankyrin-G and may regulate the migration of vascular endothelial cells and affect cell–cell junctions. Therefore, the variation p.R1468H may cause weakening of the artery walls, thereby accelerating the formation of IA. Thus, ANK3 is a candidate gene highly related to IA.

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“…Lens epithelial morphogenesis, polarity and cell-cell junction integrity have been demonstrated to be regulated by actin cytoskeletal organization, non-muscle myosin II, integrins, ankyrin-G and Rho, Rac and Rap1 GTP ases 3,6,[8][9][10][11][12]26,36 . Additionally, disruption of lens epithelial actin cytoskeletal organization, polarity and cell-cell junctional integrity have been recognized to impair epithelial morphogenesis, induce EMT and increase production of extracellular matrix 8,9,12,37 . Interestingly, development of posterior capsular cataracts (PCO) is a very common secondary pathology in patients with intraocular lenses, and is associated with altered lens epithelial plasticity and EMT 38,39 .…”

Section: Discussionmentioning

confidence: 99%

“…Cytoskeletal and cytoskeletal-interacting proteins including actin, myosin, spectrin, integrins, catenins, scaffolding proteins and signaling proteins regulating the actin cytoskeleton networks have been demonstrated to be required for maintenance of lens epithelial phenotype, proliferation, differentiation and survival 3,5-7 . Although dysregulation of actomyosin organization, cell adhesion and cell-cell junctions is recognized to influence lens epithelial plasticity and result in transdifferentiation of lens epithelial cells into matrix open Scientific RepoRtS | (2020) 10:1295 | https://doi.org/10.1038/s41598-020-58189-y www.nature.com/scientificreports www.nature.com/scientificreports/ producing myofibroblasts (EMT), there are gaps in our understanding of the proteins that interact with and regulate the organization and contractile characteristics of actin and myosin [8][9][10][11][12] .Calponin is a well-characterized actin, myosin, tropomyosin and calcium/calmodulin binding contractile protein that inhibits actin-dependent activity of myosin Mg 2+ ATPase 13,14 . Calponin exists as three isoforms (basic, CNN1; neutral, CNN2 and acidic, CNN3) encoded by independent genes 13 .…”

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confidence: 99%

Calponin-3 deficiency augments contractile activity, plasticity, fibrogenic response and Yap/Taz transcriptional activation in lens epithelial cells and explants

Maddala

Mongan

Xia

et al. 2020

Sci Rep

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The transparent ocular lens plays a crucial role in vision by focusing light on to the retina with loss of lens transparency leading to impairment of vision. While maintenance of epithelial phenotype is recognized to be essential for lens development and function, knowledge of the identity of different molecular mechanisms regulating lens epithelial characteristics remains incomplete. This study reports that CNN-3, the acidic isoform of calponin, an actin binding contractile protein, is expressed preferentially and abundantly relative to the basic and neutral isoforms of calponin in the ocular lens, and distributes predominantly to the epithelium in both mouse and human lenses. Expression and MEKK1-mediated threonine 288 phosphorylation of CNN-3 is induced by extracellular cues including TGF-β2 and lysophosphatidic acid. Importantly, siRNA-induced deficiency of CNN3 in lens epithelial cell cultures and explants results in actin stress fiber reorganization, stimulation of focal adhesion formation, Yap activation, increases in the levels of α-smooth muscle actin, connective tissue growth factor and fibronectin, and decreases in E-cadherin expression. These results reveal that CNN3 plays a crucial role in regulating lens epithelial contractile activity and provide supporting evidence that CNN-3 deficiency is associated with the induction of epithelial plasticity, fibrogenic activity and mechanosensitive Yap/Taz transcriptional activation.The avascular transparent ocular lens plays a crucial role in vision by focusing incident light on to the retina and aberrations in lens transparency (cataract) impair vision. Cataract is a leading cause of blindness in the ageing population throughout the world, and surgical replacement of opaque or cloudy lens with artificial lenses is the only treatment option available for restoration of vision in patients 1,2 . Thus, a detailed understanding of lens growth and function would provide insights into developing medical therapies to delay lens opacification. The ocular lens is located behind the cornea and iris in the anterior chamber of eye, suspended by zonules attached to the ciliary muscle. Following its development from the surface ectoderm, the lens continues to grow throughout life, with the adult lens being composed of an epithelial monolayer covering the anterior surface and fiber cells differentiated from the equatorial epithelium constituting the bulk of the lens 3,4 . The lens is encapsulated by a thick basement membrane termed the capsule and consisting of extracellular matrix. Cuboidal epithelial cells in the adult lens maintain characteristic E-cadherin and N-cadherin-based cell-cell junctions, tight junctions and apical and basal polarity 3 . Cytoskeletal and cytoskeletal-interacting proteins including actin, myosin, spectrin, integrins, catenins, scaffolding proteins and signaling proteins regulating the actin cytoskeleton networks have been demonstrated to be required for maintenance of lens epithelial phenotype, proliferation, differentiation and survival 3,5-7 . ...

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Ankyrin-G regulated epithelial phenotype is required for mouse lens morphogenesis and growth

Cited by 6 publications

References 43 publications

Drebrin, an actin‐binding protein, is required for lens morphogenesis and growth

Drebrin, an actin‐binding protein, is required for lens morphogenesis and growth

A Rare Variant of ANK3 Is Associated With Intracranial Aneurysm

Calponin-3 deficiency augments contractile activity, plasticity, fibrogenic response and Yap/Taz transcriptional activation in lens epithelial cells and explants

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