Yang Sun

All Publications

• Review of Ocular Manifestations of Joubert Syndrome. Genes Wang, S. F., Kowal, T. J., Ning, K., Koo, E. B., Wu, A. Y., Mahajan, V. B., Sun, Y. 2018; 9 (12)

  Abstract

  Joubert syndrome is a group of rare disorders that stem from defects in a sensory organelle, the primary cilia. Affected patients often present with disorders involving multiple organ systems, including the brain, eyes, and kidneys. Common symptoms include breathing abnormalities, mental developmental delays, loss of voluntary muscle coordination, and abnormal eye movements, with a diagnostic "molar tooth" sign observed by magnetic resonance imaging (MRI) of the midbrain. We reviewed the ocular phenotypes that can be found in patients with Joubert syndrome. Ocular motor apraxia is the most frequent (80% of patients), followed by strabismus (74%) and nystagmus (72%). A minority of patients also present with ptosis (43%), chorioretinal coloboma (30%), and optic nerve atrophy (22%). Although mutations in 34 genes have been found to be associated with Joubert syndrome, retinal degeneration has been reported in only 38% of patients. Mutations in AHI1 and CEP290, genes critical to primary cilia function, have been linked to retinal degeneration. In conclusion, Joubert syndrome is a rare pleiotropic group of disorders with variable ocular presentations.

  View details for DOI 10.3390/genes9120605

  View details for PubMedID 30518138

• Coordination of Necessary and Permissive Signals by PTEN Inhibition for CNS Axon Regeneration FRONTIERS IN NEUROSCIENCE Zhang, J., Yang, D., Huang, H., Sun, Y., Hu, Y. 2018; 12

  View details for DOI 10.3389/fnins.2018.00558

  View details for Web of Science ID 000441431700001

• Ocular and renal phenotypes of NPHP1 deletion in Senior Loken syndrome Ning, K., Song, E., Haider, K. M., Ghaffarieh, A., Alvarado, J. A., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442932805425

• Single particle tracking of nicotinic acetylcholine receptors (AChRs): implication for the pathogenesis of ocular myasthenia gravis (MG) He, W., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442912500291

• The role of inositol phosphatase OCRL in microtubule nucleation: Implications for Oculocerebrorenal Syndrome of Lowe Wang, B., Prosseda, P. P., He, W., Kowal, T., Alvarado, J. A., Ning, K., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442912509107

• Optogenetic Regulation of Aqueous Outflow in Mouse Trabecular Meshwork Alvarado, J. A., Prosseda, P. P., Luo, N., Wang, B., Ning, K., He, W., Kowal, T., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442932804178

• Intraluminal Deposits Found in Glaucoma Tube Shunts Via Anterior Segment Ocular Coherence Tomography JOURNAL OF GLAUCOMA Alvarado, J. A., Srivastava, V., Sun, Y. 2018; 27 (3): E68–E71

  Abstract

  To describe and characterize a novel observation of intraluminal deposits of glaucoma tube shunts (TS) using spectral domain (SD) ocular coherence topography (OCT).Fifteen TS in 11 patients diagnosed with primary open-angle, neovascular, aphakic, and uveitic glaucomas. Both Ahmed (n=11) and Baerveldt (n=4) TS were examined with 5-line raster anterior segment SD-OCT imaging.The exposed tubes of 2 patients had highly reflective intraluminal deposits in the corresponding exposed areas. Seven tubes without exposure had a thin rim of highly reflective material. Six tubes were clear of luminal deposits. The most common diagnosis in the study was uveitic glaucoma which occurred in 5 of the 15 eyes (33%). The next most common diagnosis was primary open-angle glaucoma which occurred in 4 of the 15 eyes (25%). There were 2 nonvalved Baerveldt tubes in each group. The mean duration of TS implantation was 15.0 months in the deposit group and 33.7 months in the group without luminal deposits. The majority of patients in each group were using eye drops at presentation (88.9% deposit, 83.3% clear), and the average intraocular pressure was 20.2 mm Hg in the deposit group and 19.0 mm Hg in the clear group.Anterior segment OCT imaging may be used to evaluate TS integrity. Intraluminal deposits in TS may occur as a natural response to implanted drainage device, possibly as an inflammatory response.

  View details for DOI 10.1097/IJG.0000000000000840

  View details for Web of Science ID 000428803500005

  View details for PubMedID 29240598

  View details for PubMedCentralID PMC5831525

• Proteomic analysis of the human retina reveals region-specific susceptibilities to metabolic-and oxidative stress-related diseases PLOS ONE Velez, G., Machlab, D. A., Tang, P. H., Sun, Y., Tsang, S. H., Bassuk, A. G., Mahajan, V. B. 2018; 13 (2): e0193250

  Abstract

  Differences in regional protein expression within the human retina may explain molecular predisposition of specific regions to ophthalmic diseases like age-related macular degeneration, cystoid macular edema, retinitis pigmentosa, and diabetic retinopathy. To quantify protein levels in the human retina and identify patterns of differentially-expressed proteins, we collected foveomacular, juxta-macular, and peripheral retina punch biopsies from healthy donor eyes and analyzed protein content by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Protein expression was analyzed with 1-way ANOVA, gene ontology, pathway representation, and network analysis. We identified a mean of 1,974 proteins in the foveomacular retina, 1,999 in the juxta-macular retina, and 1,779 in the peripheral retina. Six hundred ninety-seven differentially-expressed proteins included those unique to and abundant in each anatomic region. Proteins with higher expression in each region include: heat-shock protein 90-alpha (HSP90AA1), and pyruvate kinase (PKM) in the foveomacular retina; vimentin (VIM) and fructose-bisphosphate aldolase C (ALDOC); and guanine nucleotide-binding protein subunit beta-1 (GNB1) and guanine nucleotide-binding protein subunit alpha-1 (GNAT1) in the peripheral retina. Pathway analysis identified downstream mediators of the integrin signaling pathway to be highly represented in the foveomacular region (P = 6.48 e-06). Metabolic pathways were differentially expressed among all retinal regions. Gene ontology analysis showed that proteins related to antioxidant activity were higher in the juxta-macular and the peripheral retina, but present in lower amounts in the foveomacular retina. Our proteomic analysis suggests that certain retinal regions are susceptible to different forms of metabolic and oxidative stress. The findings give mechanistic insight into retina function, reveal important molecular processes, and prioritize new pathways for therapeutic targeting.

  View details for DOI 10.1371/journal.pone.0193250

  View details for Web of Science ID 000425604300103

  View details for PubMedID 29466423

  View details for PubMedCentralID PMC5821407

• Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome. Journal of cell science Prosseda, P. P., Luo, N., Wang, B., Alvarado, J. A., Hu, Y., Sun, Y. 2017; 130 (20): 3447–54

  Abstract

  Lowe syndrome is a rare X-linked disorder characterized by bilateral congenital cataracts and glaucoma, mental retardation, and proximal renal tubular dysfunction. Mutations in OCRL, an inositol polyphosphate 5-phosphatase that dephosphorylates PI(4,5)P2, cause Lowe syndrome. Previously we showed that OCRL localizes to the primary cilium, which has a distinct membrane phospholipid composition, but disruption of phosphoinositides in the ciliary membrane is poorly understood. Here, we demonstrate that cilia from Lowe syndrome patient fibroblasts exhibit increased levels of PI(4,5)P2 and decreased levels of PI4P. In particular, subcellular distribution of PI(4,5)P2 build-up was observed at the transition zone. Accumulation of ciliary PI(4,5)P2 was pronounced in mouse embryonic fibroblasts (MEFs) derived from Lowe syndrome mouse model as well as in Ocrl-null MEFs, which was reversed by reintroduction of OCRL. Similarly, expression of wild-type OCRL reversed the elevated PI(4,5)P2 in Lowe patient cells. Accumulation of sonic hedgehog protein in response to hedgehog agonist was decreased in MEFs derived from a Lowe syndrome mouse model. Together, our findings show for the first time an abnormality in ciliary phosphoinositides of both human and mouse cell models of Lowe syndrome.

  View details for DOI 10.1242/jcs.200857

  View details for PubMedID 28871046

• Primary cilia signaling mediates intraocular pressure sensation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Luo, N., Conwell, M. D., Chen, X., Kettenhofen, C. I., Westlake, C. J., Cantor, L. B., Wells, C. D., Weinreb, R. N., Corson, T. W., Spandau, D. F., Joos, K. M., Iomini, C., Obukhov, A. G., Sun, Y. 2014; 111 (35): 12871-12876

  Abstract

  Lowe syndrome is a rare X-linked congenital disease that presents with congenital cataracts and glaucoma, as well as renal and cerebral dysfunction. OCRL, an inositol polyphosphate 5-phosphatase, is mutated in Lowe syndrome. We previously showed that OCRL is involved in vesicular trafficking to the primary cilium. Primary cilia are sensory organelles on the surface of eukaryotic cells that mediate mechanotransduction in the kidney, brain, and bone. However, their potential role in the trabecular meshwork (TM) in the eye, which regulates intraocular pressure, is unknown. Here, we show that TM cells, which are defective in glaucoma, have primary cilia that are critical for response to pressure changes. Primary cilia in TM cells shorten in response to fluid flow and elevated hydrostatic pressure, and promote increased transcription of TNF-α, TGF-β, and GLI1 genes. Furthermore, OCRL is found to be required for primary cilia to respond to pressure stimulation. The interaction of OCRL with transient receptor potential vanilloid 4 (TRPV4), a ciliary mechanosensory channel, suggests that OCRL may act through regulation of this channel. A novel disease-causing OCRL allele prevents TRPV4-mediated calcium signaling. In addition, TRPV4 agonist GSK 1016790A treatment reduced intraocular pressure in mice; TRPV4 knockout animals exhibited elevated intraocular pressure and shortened cilia. Thus, mechanotransduction by primary cilia in TM cells is implicated in how the eye senses pressure changes and highlights OCRL and TRPV4 as attractive therapeutic targets for the treatment of glaucoma. Implications of OCRL and TRPV4 in primary cilia function may also shed light on mechanosensation in other organ systems.

  View details for DOI 10.1073/pnas.1323292111

  View details for Web of Science ID 000341230800077

  View details for PubMedID 25143588

• STAT6-Mediated Keratitis and Blepharitis: A Novel Murine Model of Ocular Atopic Dermatitis INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Turner, M. J., DaSilva-Arnold, S., Luo, N., Hu, X., West, C. C., Sun, L., Hall, C., Bradish, J., Kaplan, M. H., Travers, J. B., Sun, Y. 2014; 55 (6): 3803-3808

  Abstract

  Atopic dermatitis (AD) is a common inflammatory disease that can affect the eye, resulting in ocular pathologies, including blepharitis, keratitis, and uveitis; however, the pathogenic mechanisms underlying the ocular manifestations of AD are not well understood.In the present study, we characterized the ocular pathologies that develop in the Stat6VT mouse model of AD. We examined the cytokine profile of the eyelid lesions, measured the behavioral response, and documented the treatment response to topical steroids.Our results show that Stat6VT mice spontaneously developed blepharitis, keratitis, and uveitis similar to that observed in patients with AD. Histologic findings of allergic inflammation in affected eyelids in this model include the presence of a lymphocyte-predominant infiltrate and tissue eosinophilia in the dermis. Gene expression analysis of affected eyelid tissue by quantitative PCR revealed increased amounts of mRNAs for the Th2 cytokines IL-4, IL-5, and IL-13. In addition, increased eyelid scratching was seen in Stat6VT mice with blepharitis. Topical treatment with the corticosteroid clobetasol reduced eyelid inflammation, tissue eosinophilia, and Th2 cytokine expression.The development of AD-like ocular pathologies in this model supports the idea that in humans, AD-associated disease of the eye may be driven by Th2-mediated inflammation and demonstrates that the Stat6VT mouse may be a useful system in which to further investigate pathogenesis of and treatment strategies for blepharitis and other ocular diseases that develop in association with AD.

  View details for DOI 10.1167/iovs.13-13685

  View details for Web of Science ID 000339485800053

  View details for PubMedID 24845637

• Serum deprivation inhibits the transcriptional co-activator YAP and cell growth via phosphorylation of the 130-kDa isoform of Angiomotin by the LATS1/2 protein kinases PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Adler, J. J., Johnson, D. E., Heller, B. L., Bringman, L. R., Ranahan, W. P., Conwell, M. D., Sun, Y., Hudmon, A., Wells, C. D. 2013; 110 (43): 17368-17373

  Abstract

  Large tumor suppressor (LATS)1/2 protein kinases transmit Hippo signaling in response to intercellular contacts and serum levels to limit cell growth via the inhibition of Yes-associated protein (YAP). Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130. Consistently, the Amot130 (S175A) mutant, which lacks LATS phosphorylation, bound AIP4 poorly under all conditions and showed reduced stability. Amot130 and AIP4 also promoted the ubiquitination and degradation of YAP in response to serum starvation, unlike Amot130 (S175A). Moreover, silencing Amot130 expression blocked LATS1 from inhibiting the expression of connective tissue growth factor, a YAP-regulated gene. Concordant with phosphorylated Amot130 specifically mediating these effects, wild-type Amot130 selectively induced YAP phosphorylation and reduced transcription of connective tissue growth factor in an AIP4-dependent manner versus Amot130 (S175A). Further, Amot130 but not Amot130 (S175A) strongly inhibited the growth of MDA-MB-468 breast cancer cells. The dominant-negative effects of Amot130 (S175A) on YAP signaling also support that phosphorylated Amot130 transduces Hippo signaling. Likewise, Amot130 expression provoked premature growth arrest during mammary cell acini formation, whereas Amot130 (S175A)-expressing cells formed enlarged and poorly differentiated acini. Taken together, the phosphorylation of Amot130 by LATS is found to be a key feature that enables it to inhibit YAP-dependent signaling and cell growth.

  View details for DOI 10.1073/pnas.1308236110

  View details for Web of Science ID 000325943300050

  View details for PubMedID 24101513

• Compensatory Role of Inositol 5-Phosphatase INPP5B to OCRL in Primary Cilia Formation in Oculocerebrorenal Syndrome of Lowe PLOS ONE Luo, N., Kumar, A., Conwell, M., Weinreb, R. N., Anderson, R., Sun, Y. 2013; 8 (6)

  Abstract

  Inositol phosphatases are important regulators of cell signaling, polarity, and vesicular trafficking. Mutations in OCRL, an inositol polyphosphate 5-phosphatase, result in Oculocerebrorenal syndrome of Lowe, an X-linked recessive disorder that presents with congenital cataracts, glaucoma, renal dysfunction and mental retardation. INPP5B is a paralog of OCRL and shares similar structural domains. The roles of OCRL and INPP5B in the development of cataracts and glaucoma are not understood. Using ocular tissues, this study finds low levels of INPP5B present in human trabecular meshwork but high levels in murine trabecular meshwork. In contrast, OCRL is localized in the trabecular meshwork and Schlemm's canal endothelial cells in both human and murine eyes. In cultured human retinal pigmented epithelial cells, INPP5B was observed in the primary cilia. A functional role for INPP5B is revealed by defects in cilia formation in cells with silenced expression of INPP5B. This is further supported by the defective cilia formation in zebrafish Kupffer's vesicles and in cilia-dependent melanosome transport assays in inpp5b morphants. Taken together, this study indicates that OCRL and INPP5B are differentially expressed in the human and murine eyes, and play compensatory roles in cilia development.

  View details for DOI 10.1371/journal.pone.0066727

  View details for Web of Science ID 000320846500099

  View details for PubMedID 23805271

• Evidence of a role of inositol polyphosphate 5-phosphatase INPP5E in cilia formation in zebrafish VISION RESEARCH Luo, N., Lu, J., Sun, Y. 2012; 75: 98-107

  Abstract

  Inositol phosphatases are important regulators of cell signaling and membrane trafficking. Mutations in inositol polyphosphate 5-phosphatase, INPP5E, have been identified in Joubert syndrome, a rare congenital disorder characterized by midbrain malformation, retinitis pigmentosa, renal cysts, and polydactyly. Previous studies have implicated primary cilia abnormalities in Joubert syndrome, yet the role of INPP5E in cilia formation is not well understood. In this study, we examined the function of INPP5E in cilia development in zebrafish. Using specific antisense morpholino oligonucleotides to knockdown Inpp5e expression, we observed phenotypes of microphthalmia, pronephros cysts, pericardial effusion, and left-right body axis asymmetry. The Inpp5e morphant zebrafish exhibited shortened and decreased cilia formation in the Kupffer's vesicle and pronephric ducts as compared to controls. Epinephrine-stimulated melanosome trafficking was delayed in the Inpp5e zebrafish morphants. Expression of human INPP5E expression rescued the phenotypic defects in the Inpp5e morphants. Taken together, we showed that INPP5E is critical for the cilia development in zebrafish.

  View details for DOI 10.1016/j.visres.2012.09.011

  View details for Web of Science ID 000312426100015

  View details for PubMedID 23022135

• OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome HUMAN MOLECULAR GENETICS Luo, N., West, C. C., Murga-Zamalloa, C. A., Sun, L., Anderson, R. M., Wells, C. D., Weinreb, R. N., Travers, J. B., Khanna, H., Sun, Y. 2012; 21 (15): 3333-3344

  Abstract

  Oculocerebral renal syndrome of Lowe (OCRL or Lowe syndrome), a severe X-linked congenital disorder characterized by congenital cataracts and glaucoma, mental retardation and kidney dysfunction, is caused by mutations in the OCRL gene. OCRL is a phosphoinositide 5-phosphatase that interacts with small GTPases and is involved in intracellular trafficking. Despite extensive studies, it is unclear how OCRL mutations result in a myriad of phenotypes found in Lowe syndrome. Our results show that OCRL localizes to the primary cilium of retinal pigment epithelial cells, fibroblasts and kidney tubular cells. Lowe syndrome-associated mutations in OCRL result in shortened cilia and this phenotype can be rescued by the introduction of wild-type OCRL; in vivo, knockdown of ocrl in zebrafish embryos results in defective cilia formation in Kupffer vesicles and cilia-dependent phenotypes. Cumulatively, our data provide evidence for a role of OCRL in cilia maintenance and suggest the involvement of ciliary dysfunction in the manifestation of Lowe syndrome.

  View details for DOI 10.1093/hmg/dds163

  View details for Web of Science ID 000306414900003

  View details for PubMedID 22543976

• p38 phosphorylates Rb on Ser567 by a novel, cell cycle-independent mechanism that triggers Rb-Hdm2 interaction and apoptosis ONCOGENE Delston, R. B., Matatall, K. A., Sun, Y., Onken, M. D., Harbour, J. W. 2011; 30 (5): 588-599

  Abstract

  The retinoblastoma protein (Rb) inhibits both cell division and apoptosis, but the mechanism by which Rb alternatively regulates these divergent outcomes remains poorly understood. Cyclin-dependent kinases (Cdks) promote cell division by phosphorylating and reversibly inactivating Rb by a hierarchical series of phosphorylation events and sequential conformational changes. The stress-regulated mitogen-activated protein kinase p38 also phosphorylates Rb, but it does so in a cell cycle-independent manner that is associated with apoptosis rather than with cell division. Here, we show that p38 phosphorylates Rb by a novel mechanism that is distinct from that of Cdks. p38 bypasses the cell cycle-associated hierarchical phosphorylation and directly phosphorylates Rb on Ser567, which is not phosphorylated during the normal cell cycle. Phosphorylation by p38, but not Cdks, triggers an interaction between Rb and the human homolog of murine double minute 2 (Hdm2), leading to degradation of Rb, release of E2F1 and cell death. These findings provide a mechanistic explanation as to how Rb regulates cell division and apoptosis through different kinases, and reveal how Hdm2 may functionally link the tumor suppressors Rb and p53.

  View details for DOI 10.1038/onc.2010.442

  View details for Web of Science ID 000286922300007

  View details for PubMedID 20871633

• Functional analysis of the p53 pathway in response to ionizing radiation in uveal melanoma INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Sun, Y., Tran, B. N., Worley, L. A., Delston, R. B., Harbour, J. W. 2005; 46 (5): 1561-1564

  Abstract

  Uveal melanomas are notoriously radioresistant and thus necessitate treatment with extremely high radiation doses that often cause ocular complications. The p53 tumor suppressor pathway is a major mediator of the cellular response to radiation-induced DNA damage, suggesting that this pathway may be defective in uveal melanoma. The current study was conducted to analyze the functional integrity of the p53 pathway in primary uveal melanoma cells.The p53 gene was sequenced in three primary uveal melanoma cells lines. Cultured primary uveal melanoma cells (MM28, MM50, Mel202, Mel270, and Mel290), MCF7 breast carcinoma cells, normal uveal melanocytes (UM47), and normal human diploid fibroblasts (NHDFs) were irradiated at 250 kVp and 12 mA at a dose rate of 1.08 Gy/min for a total dose of up to 20 Gy. Cell viability was analyzed with trypan blue exclusion. Western blot analysis was used to analyze the expression of p53, p53-phospho-Ser15, p21, Bax, PUMA, and Bcl-x(L).No p53 gene mutations were found in MM28, MM50, or Mel270 cells. Upstream signaling to p53 was intact, with normal induction of p53 and phosphorylation of p53-Ser15, in all five cell lines. Radiation-induced downstream activation of p21 was defective in MM28 and MM50 cells, and activation of Bax was defective in MM50 and Mel290 cells. MM28, MM50, and Mel202 cells failed to deamidate Bcl-x(L) in response to radiation-induced DNA damage. Overall, four of the five uveal melanoma cell lines exhibited at least one downstream defect in the p53 pathway.Expression of p53 and upstream signaling to p53 in response to radiation-induced DNA damage appear to be intact in most uveal melanomas. In contrast, functional defects in the p53 pathway downstream of p53 activation appear to be common. Further elucidation of p53 pathway abnormalities in uveal melanoma may allow therapeutic interventions to increase the radiosensitivity of the tumors.

  View details for DOI 10.1167/iovs.04-1362

  View details for Web of Science ID 000228708000005

  View details for PubMedID 15851551