Genetic Deletion of Laminin Isoforms β2 and γ3 Induces a Reduction in Kir4.1 and Aquaporin-4 Expression and Function in the Retina

Hirrlinger, Petra G.; Pannicke, Thomas; Winkler, Ulrike; Claudepierre, Thomas; Varshney, Shweta; Schulze, Christine; Reichenbach, Andreas; Brunken, William J.; Hirrlinger, Johannes

doi:10.1371/journal.pone.0016106

Cited by 30 publications

(31 citation statements)

References 51 publications

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“…Prior studies have shown that Kir4.1 and AQP4 associate with the Dp71‐dependent DAPs complex at the Müller cell endfeet and that this complex associates with laminin through β‐dystroglycan (Hirrlinger et al, ) (Fig. G).…”

Section: Resultsmentioning

confidence: 85%

AAV‐mediated gene delivery in Dp71‐null mouse model with compromised barriers

Vacca

Darche

Schaffer

et al. 2013

Glia

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Formation and maintenance of the blood–retinal barrier (BRB) is required for proper vision and breaching of this barrier contributes to the pathology in a wide variety of retinal conditions such as retinal detachment and diabetic retinopathy. Dystrophin Dp71 being a key membrane cytoskeletal protein, expressed mainly in Müller cells, its absence has been related to BRB permeability through delocalization and down‐regulation of the AQP4 and Kir4.1 channels. Dp71‐null mouse is thus an excellent model to approach the study of retinal pathologies showing blood–retinal barrier permeability. We aimed to investigate the participation of Müller cells in the BRB and in the inner limiting membrane of Dp71‐null mice compared with wild‐type mice in order to understand how these barriers work in this model of permeable BRB. To this aim, we used an Adeno‐associated virus (AAV) variant, ShH10‐GFP, engineered to target Müller cells specifically. ShH10 coding GFP was introduced by intravitreal injection and Müller cell transduction was studied in Dp71‐null mice in comparison to wild‐type animals. We show that Müller cell transduction follows a significantly different pattern in Dp71‐null mice indicating changes in viral cell‐surface receptors as well as differences in the permeability of the inner limiting membrane in this mouse line. However, the compromised BRB of the Dp71‐null mice does not lead to virus leakage into the bloodstream when the virus is injected intravitreally – an important consideration for AAV‐mediated retinal gene therapy. GLIA 2014;62:468–476

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Section: Resultsmentioning

confidence: 85%

AAV‐mediated gene delivery in Dp71‐null mouse model with compromised barriers

Vacca

Darche

Schaffer

et al. 2013

Glia

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“…2J,K), whereas the ILM from Lamb2 and Lamb2:c3-null retinae had a lattice-like appearance with large holes (Fig. 2L,M) (see also Hirrlinger et al, 2011).…”

Section: Research Articlementioning

confidence: 81%

“…In the retina, laminins are crucial for ILM formation (Pinzón-Duarte et al, 2010;Hirrlinger et al, 2011;Halfter et al, 2005;Edwards et al, 2010). Similarly, mutations in α-dystroglycan (a laminin receptor) and in an enzyme that participates in glycosylation of α-dystroglycan (POMGnT1) also produce defective deposition of laminin at the ILM, resulting in defective ILM formation Takahashi et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Laminins containing the β2 and γ3 chains regulate astrocyte migration and angiogenesis in the retina

et al. 2013

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SUMMARYPathologies of retinal blood vessels are among the major causes of blindness worldwide. A key cell type that regulates retinal vascular development is the astrocyte. Generated extrinsically to the retina, astrocytes migrate into the retina through the optic nerve head. Even though there is a strong correlation between astrocyte distribution and retinal vascular development, the factors that guide astrocytes into the retina remain unclear. In this study, we show that astrocytes migrate within a laminin-containing basement membrane -the inner limiting membrane. Genetic deletion of the laminin β2 and γ3 chains affects astrocyte migration and spatial distribution. We show that laminins act as haptotactic factors in vitro in an isoform-specific manner, inducing astrocyte migration and promoting astrocyte differentiation. The addition of exogenous laminins to laminin-null retinal explants rescues astrocyte migration and spatial patterning. Furthermore, we show that the loss of laminins reduces β1 integrin expression in astrocytes. Culturing lamininnull retinal astrocytes on laminin substrates restores focal localization of β1 integrin. Finally, we show that laminins containing β2 and γ3 chains regulate subsequent retinal blood vessel growth and maintain vascular integrity. These in vivo and in vitro studies demonstrate clearly that laminins containing β2 and γ3 chains are indispensable for migration and spatial organization of astrocytes and that they play a crucial role during retinal angiogenesis in vivo. RESEARCH ARTICLELaminins regulate angiogenesis treatment with exogenous laminins rescues astrocyte migration and spatial patterning phenotype ex vivo. Together, these data support the hypothesis that β2-and γ3-containing laminins are important cues in retinal vascular development.

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“…Interestingly, the downregulation of Kir channels pushes the M€ uller glia towards the proliferative stage (Jadhav et al, 2009). In conjunction with these findings, Hirrlinger et al demonstrated that the genetic deletion of both b2-and c3-laminins leads to diminished functions of the Kir4.1 potassium and aquaporin-4 water channel in M€ uller glia cells (Hirrlinger et al, 2011). Based on these findings, laminins might have a great impact on M€ uller glia proliferation and gliosis.…”

Section: Expression Of Ecm Constituents In the Retinal Stem Cell Nichementioning

confidence: 92%

The extracellular matrix compartment of neural stem and glial progenitor cells

Faissner

Reinhard

2015

Glia

100

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Neuroepithelial and radial GLIA stem cells generate the majority of the cellular constituents of the central nervous system. Following precisely timed phases of neurogenesis and gliogenesis the stem cells recede, with the exception of adult neural stem cells that persist in two generally accepted canonical neurogenic regions, the subventricular zone of the lateral ventricle and the subgranular zone in the dentate gyrus of the hippocampus. It is believed that adult stem cells reside in privileged stem cell niche environments that provide favorable conditions for self-renewal and maintenance of this cellular compartment. Factors such as morphogens, cytokines, and growth factors influence the developmental pathway of neural stem/progenitor cells. By comparison, less is known about the regulatory roles of glycoproteins and proteoglycans of the extracellular matrix (ECM) and their receptors, although they represent important constituents of the micromolecular environment of the niche. Here, we summarize studies that indicate pivotal roles of the ECM micromilieu for the biology and instrumental use of glial stem and progenitor cells of the CNS. Advancing our understanding of structure-function relationships, signaling motifs and complementary receptors and their signal transduction pathways will be of central importance for the application of these cell types in regenerative medicine.

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Genetic Deletion of Laminin Isoforms β2 and γ3 Induces a Reduction in Kir4.1 and Aquaporin-4 Expression and Function in the Retina

Cited by 30 publications

References 51 publications

AAV‐mediated gene delivery in Dp71‐null mouse model with compromised barriers

AAV‐mediated gene delivery in Dp71‐null mouse model with compromised barriers

Laminins containing the β2 and γ3 chains regulate astrocyte migration and angiogenesis in the retina

The extracellular matrix compartment of neural stem and glial progenitor cells

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