Absence of S100A4 in the mouse lens induces an aberrant retina-specific differentiation program and cataract.
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2021-01-26
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S100A4, a member of the S100 family of multifunctional calcium-binding proteins, participates in several physiological and pathological processes. In this study, we demonstrate that S100A4 expression is robustly induced in differentiating fiber cells of the ocular lens and that S100A4 (-/-) knockout mice develop late-onset cortical cataracts. Transcriptome profiling of lenses from S100A4 (-/-) mice revealed a robust increase in the expression of multiple photoreceptor- and Müller glia-specific genes, as well as the olfactory sensory neuron-specific gene, S100A5. This aberrant transcriptional profile is characterized by corresponding increases in the levels of proteins encoded by the aberrantly upregulated genes. Ingenuity pathway network and curated pathway analyses of differentially expressed genes in S100A4 (-/-) lenses identified Crx and Nrl transcription factors as the most significant upstream regulators, and revealed that many of the upregulated genes possess promoters containing a high-density of CpG islands bearing trimethylation marks at histone H3K27 and/or H3K4, respectively. In support of this finding, we further documented that S100A4 (-/-) knockout lenses have altered levels of trimethylated H3K27 and H3K4. Taken together, our findings suggest that S100A4 suppresses the expression of retinal genes during lens differentiation plausibly via a mechanism involving changes in histone methylation.
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Maddala, Rupalatha, Junyuan Gao, Richard T Mathias, Tylor R Lewis, Vadim Y Arshavsky, Adriana Levine, Jonathan M Backer, Anne R Bresnick, et al. (2021). Absence of S100A4 in the mouse lens induces an aberrant retina-specific differentiation program and cataract. Scientific reports, 11(1). p. 2203. 10.1038/s41598-021-81611-y Retrieved from https://hdl.handle.net/10161/22327.
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Scholars@Duke
Rupalatha Maddala
Dr. Maddala was recently promoted to Associate Professor of Ophthalmology following her
post-doctoral fellowship and research scientist roles in the Rao Laboratory. She has a keen
interest in fundamental biological research. Her research is focused on ocular lens and
glaucoma. Dr. Maddala's post doctorial research demonstrated the essential role of Rho, Rac
and Rap1 GTPases in lens development and function.
During her time as a research scientist, her research discovered that the lens expresses S100A4,
a small molecular calcium binding protein which exhibits a lens fiber cell-specific, discrete
distribution profile, an independent research project that was NIH-funded.
Dr. Maddala’s long term plans include understanding lens and trabecular meshwork (TM)
biology and function as they relate to ocular dysfunction and identification of new therapies to
address unmet needs in ocular disease. She has been invited to present her research at ISER
meetings in Berlin and Montreal, Lens and Cataract meeting of NFER in Hawaii and ARVO
annual conferences. She also enjoys teaching undergraduate, medical and postdoctorial
students.
Vadim Y Arshavsky
The Biology and Pathophysiology of Vertebrate Photoreceptor Cells
Research conducted in our laboratory is dedicated to understanding how vision is performed on the molecular level. Most of our work is centered on vertebrate photoreceptor cells, which are sensory neurons responsible for light detection in the eye. Photoreceptors capture photons, produce an electrical signal, and transmit this information to the secondary neurons in the retina, and ultimately to the brain, through modulation of their synaptic release.
The main experimental direction of our laboratory is to elucidate the cellular processes responsible for building the light-sensitive organelle of photoreceptor cells, called the outer segment, and for populating this organelle with proteins supporting its structure and conducting visual signaling. Of particular interest is the mechanism by which outer segments form their “disc” membrane stacks providing vast membrane surfaces for efficient photon capture. Outer segment membranes are continuously renewed throughout the lifetime of a photoreceptor, with new discs added to the outer segment base and old discs phagocytosed at the tip by the retinal pigment epithelium. As a result, the entire mammalian outer segment is replaced with new discs over the course of 8-10 days. One of the central goals of our current studies is to elucidate the signaling pathway that acts as a “control center” to initiate the formation of each new disc with the strikingly regular frequency of approximately 80 times per day.
Our second major research direction explores a connection between understanding the basic function of rods and cones and practical, translational ideas aiming to ameliorate retinal degeneration caused by mutations in critical photoreceptor-specific proteins. Several years ago, we found that photoreceptors bearing a broad spectrum of disease-associated mutations suffer from a common cellular stress factor, proteasomal overload, i.e. insufficient ability of the ubiquitin-proteasome system to process misfolded and/or mislocalized proteins produced in these cells. Our more recent data demonstrate that the enhancement of protein degradation machinery in these cells causes a remarkable delay in the progression of photoreceptor degeneration. We continue investigating photoreceptor proteostasis in further mechanistic depth and seek optimal strategies to employ proteasomal activation as a means to ameliorate or cure inherited blindness.
During our studies, we explore high-end applications of mass spectrometry-based proteomics and were the first laboratory adopting several advanced proteomic approaches to vision research. Of particular significance are the applications of so-called “label-free” quantitative proteomics for simultaneous elucidation of multiple protein distributions among different compartments of the photoreceptor cells and for identification of unique protein components of various photoreceptor membranes. Using label-free proteomics, we demonstrated that a small protein PRCD (progressive rod and cone degeneration) is a unique component of photoreceptor discs and subsequently identified several novel unique components of the plasma membrane enclosing the rod outer segment. Most recently, we adopted a highly efficient and accurate methodology for simultaneous absolute quantification of several dozen proteins, termed MS Western. This method allowed us to determine the precise molar ratio amongst all major functional and structural proteins residing in the light-sensitive outer segments of photoreceptor cells.
Ponugoti Vasantha Rao
Research in our laboratory focuses on two areas of ocular diseases- cataract and glaucoma.
As it relates to lens biology, we are investigating cytoskeletal signaling pathways critical for lens development, cytoarchitecture, shape and function. Ongoing studies are focused on identification and characterization of plasma membrane cytoskeletal scaffolding proteins (e.g. Periaxin, ankyrins and dystrophin/dystroglycan) involved in regulation of lens fiber cell shape, alignment, tensile properties, membrane domain organization and channel protein activity, and to determine how dysregulation of membrane cytoskeletal scaffolding activity impacts these determinants of lens structure and function. Our studies are based on using both in vitro and in vivo models, and application of high resolution microscopy, mass spectrometry, biochemical and gene targeting approaches.
In the context of glaucoma, we are exploring the cellular and molecular mechanisms involved in homeostasis of intraocular pressure and aqueous humor drainage with the ultimate goal of identifying novel molecular targets upon which to base the design of therapeutic glaucoma treatments. Our laboratory is currently studying the extracellular and intracellular mechanisms (e.g. GDF-15, extracellular kinases and phosphatases, Rho GTPase/Rho kinase and the Autotaxin-LPA axis) that control cell morphology, cell adhesive interactions, plasticity, transdifferentiation, extracellular matrix synthesis, phosphorylation and organization, fibrosis and contractile properties of the trabecular meshwork, and aqueous humor outflow and intraocular pressure. These studies utilize both in vitro and in vivo models, and a combination of trabecular meshwork-derived primary cultures, perfusion studies, high resolution microscopy, mass spectrometry, biochemical, physiological and gene targeting approaches.
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