The Muller cells (MCs) have a key role in retinal homeostasis. They are polarized with an apical compartment facing the subretinal space, and a basal surface adhering to the inner limiting membrane (ILM). Disruption of either compartment leads to activation of MCs and pathobiological consequences leading to vision loss. Laminins organize basement membranes (BM), such as the ILM serving as attachment sites for cell adhesion, polarity and proliferation. We produced mice with null mutations in two laminin genes, Lamb2 and Lamc3, and found that these molecules are necessary for normal retinal development. The defects in the Lamb2/c3 nulls include: ILM malformation;MC disorganization;photoreceptor dysgenesis;and progressive pathology in the inner retina. Our long-range goal is to understand the molecular contributions of laminin to the development and stability of MC organization, in particular, as it relates to the functional architecture. Our immediate goal is to assess the organizing hypothesis that MC-laminin interactions are critical for: 1) establishing MC polarity;2) maintaining MC sub cellular organization and 3) stabilizing the structural integrity of the retina.
In Aim 1, we will examine the molecular mechanisms underlying laminin- mediated scaffolding in the MC. We will answer the following three questions. First, we will address: What Is The Molecular Organization Of The Adhesion Complex Of The MC Basal Endfoot? Next, we will determine: What Is The Laminin Dependence Of Ion Channel Sub cellular Localization And Function? Finally, we will investigate: What Is The Mechanism Of Laminin Regulation Of MC Proliferation? In Aim 2, we will examine the corollary hypothesis that the loss of adhesion to laminin substrates disrupts the normal structure/function relationships in the inner retina. Our data show that the Lamb2/c3 null animals have selective disruptions in the IPL. We will answer the following questions. First, we will ask: What Is The Laminin Dependence Of Dendritogenesis In The IPL? Next, we will address: What Are The Mechanisms Of Progressive Retinal Ganglion Cell Loss in Lamb2/Lamc3 nulls? These experiments and the molecular mechanisms they reveal will contribute to our understanding of the pathophysiology of gliosis;proliferative vitreoretinopathy and congenital ocular disorders including Walker-Warburg, Bardet-Biedl, Pierson Syndrome.

Public Health Relevance

Congenital birth defects affect millions of Americans and people world-wide. These diseases include muscular dystrophy, brain and eye disorders leading to mental retardation and blindness. This project investigates the cause of several of these diseases and the results will lead to new diagnostics and therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012676-12
Application #
8298181
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
2000-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
12
Fiscal Year
2012
Total Cost
$382,800
Indirect Cost
$142,800
Name
Suny Downstate Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
040796328
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
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Gnanaguru, Gopalan; Bachay, Galina; Biswas, Saptarshi et al. (2013) Laminins containing the ?2 and ?3 chains regulate astrocyte migration and angiogenesis in the retina. Development 140:2050-60
Pinzon-Duarte, German; Daly, Gerard; Li, Yong N et al. (2010) Defective formation of the inner limiting membrane in laminin beta2- and gamma3-null mice produces retinal dysplasia. Invest Ophthalmol Vis Sci 51:1773-82
Nakamura, Rei E I; Hunter, Dale D; Yi, Hyun et al. (2007) Identification of two novel activities of the Wnt signaling regulator Dickkopf 3 and characterization of its expression in the mouse retina. BMC Cell Biol 8:52
Denes, Viktoria; Witkovsky, Paul; Koch, Manuel et al. (2007) Laminin deficits induce alterations in the development of dopaminergic neurons in the mouse retina. Vis Neurosci 24:549-62
Aisenbrey, Sabine; Zhang, Minlei; Bacher, Daniel et al. (2006) Retinal pigment epithelial cells synthesize laminins, including laminin 5, and adhere to them through alpha3- and alpha6-containing integrins. Invest Ophthalmol Vis Sci 47:5537-44
Claudepierre, Thomas; Manglapus, Mary K; Marengi, Nathan et al. (2005) Collagen XVII and BPAG1 expression in the retina: evidence for an anchoring complex in the central nervous system. J Comp Neurol 487:190-203