Alexander I Son

Rutgers, The State University of New Jersey, Нью-Брансуик, New Jersey, United States

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Publications (10)30.93 Total impact

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    ABSTRACT: Follicle growth and ovulation involve the coordinated expression of many genes, driven by follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Reports indicate that Eph receptors and ephrins are expressed in the ovary, suggesting roles in follicle growth and/or ovulation. We previously reported FSH-induced expression of ephrin-A5 and four of its cognate Eph receptors in mouse granulosa cells. We now report that female mice lacking ephrin-A5 are subfertile, exhibit a compromised response to LH, and display abnormal ovarian histology following superovulation. Efna5(-/-) females litters were 40% smaller than controls, although no difference in litter frequency was detected. The ovarian response to superovulation was also compromised in Efna5(-/-) females, with 37% fewer oocytes ovulated than controls. These results corresponded with a reduction in ovarian mRNA levels of several LH-responsive genes, including Pgr, Ptgs2, Tnfaip6, Ereg, Btc, and Adamts4, suggesting that Efna5(-/-) ovaries exhibit a partially attenuated response to luteinizing hormone. Histopathological analysis indicated that superovulated Efna5(-/-) females exhibited numerous ovarian defects, including intraovarian release of cumulus oocyte complexes (COCs), increased incidence of oocytes trapped within luteinized follicles, granulosa cell and follicular fluid emboli, fibrin thrombi and interstitial hemorrhage. In addition, adult Efna5(-/-) ovaries exhibited a 4-fold increase in multi-oocyte follicles (MOFs) compared to controls, although no difference was detected in 3 week-old mice, suggesting the possibility of follicle merging. Our observations indicate that loss of ephrin-A5 in female mice results in subfertility, and imply that Eph-ephrin signaling may also play a previously-unidentified role in the regulation of fertility in women.
    No preview · Article · Dec 2015 · Endocrinology
  • Sondip Biswas · Alexander Son · Qili Yu · Renping Zhou · Woo-Kuen Lo
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    ABSTRACT: Ephrin-A5, a ligand of the Eph family of receptor tyrosine kinases, plays a key role in lens fiber cell packing and cell-cell adhesion, with approximately 87% of ephrin-A5(-/-) mice develop nuclear cataracts. Here, we investigated the extensive formation of light-scattering globules associated with breakdown of interlocking protrusions during lens opacification in ephrin-A5(-/-) mice. Lenses from wild-type (WT) and ephrin-A5(-/-) mice between 2 - 21 weeks old were studied with light and electron microscopy, immunofluorescence labeling, freeze-fracture TEM and filipin cytochemistry for membrane cholesterol detection. Lens opacities with various densities were first observed in ephrin-A5(-/-) mice at around 60 days old. Dense cataracts in the mutant lenses were seen primarily in the nuclear region surrounded by transparent cortices from all eyes examined. We confirmed that a majority of nuclear cataracts were dislocated posteriorly and ruptured the thinner posterior lens capsule. SEM analysis indicated that numerous interlocking protrusions and wavy ridge-and-valley membrane surfaces in deep cortical and nuclear fibers did not cause lens opacity in both transparent ephrin-A5(-/-) and WT mice. In contrast, abundant isolated membranous globules of approximately 1,000 nm in size were distributed randomly along the intact fiber cells during early stage of all ephrin-A5(-/-) cataracts examined. A further examination using both SEM and TEM revealed that isolated globules were generated from the disintegrated interlocking protrusions originally located along the corners of hexagonal fiber cells. Freeze-fracture TEM further revealed the association of square-array aquaporin junctions with both isolated globules and interlocking membrane domains. This study reports for the first time that disrupted interlocking protrusions are the source of numerous large membranous globules that contribute to light scattering and nuclear cataracts in the ephrin-A5(-/-) mice. Our results further suggest that dissociations of N-cadherin and adherens junctions in the associated interlocking domains may result in the formation of isolated globules and nuclear opacities in the ephrin-A5(-/-) mice.
    No preview · Article · Nov 2015 · Experimental Eye Research
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    ABSTRACT: Purpose: Primary vitreous regression is a critical event in mammalian eye development required for proper ocular maturity and unhindered vision. Failure of this event results in the eye disease persistent hyperplastic primary vitreous (PHPV), also identified as persistent fetal vasculature (PFV), a condition characterized by the presence of a fibrovascular mass adjacent to the lens and retina, and associated with visual disability and blindness. Here, we identify ephrin-A5 to be a critical regulator for primary vitreous regression. Methods: Wild-type and ephrin-A5(-/-) eyes were examined at various developmental stages to determine the progression of PHPV. Eye tissue was sectioned and examined by H&E staining. Protein expression and localization was determined through immunohistochemistry. Relative levels of Eph receptors were determined by RT-PCR. Results: Ephrin-A5(-/-) animals develop ocular phenotypes representative of PHPV, most notably the presence of a large hyperplastic mass posterior to the lens that remains throughout the lifetime of the animal. The aberrant tissue in these mutant mice consists of residual hyaloid vessels surrounded by pigmented cells of neural crest origin. Labeling with bromodeoxyuridine (BrdU) and detection of proliferating cell nuclear antigen (PCNA) expression shows that the mass in ephrin-A5(-/-) animals is mitotically active in embryonic and postnatal stages. Conclusions: Ephrin-A5 is a critical factor that regulates primary vitreous regression.
    No preview · Article · Feb 2014 · Investigative ophthalmology & visual science
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    Jeong Eun Park · Alexander I Son · Renping Zhou
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    ABSTRACT: The Eph family of receptor tyrosine kinases (RTKs) has been implicated in the regulation of many aspects of mammalian development. Recent analyses have revealed that the EphA2 receptor is a key modulator for a wide variety of cellular functions. This review focuses on the roles of EphA2 in both development and disease.
    Full-text · Article · Sep 2013 · Genes
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    Xin Yue · Alexander I Son · Renping Zhou
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    ABSTRACT: Growth cone collapse is an easy and efficient test for detecting and characterizing axon guidance activities secreted or expressed by cells. It can also be used to dissect signaling pathways by axon growth inhibitors and to isolate therapeutic compounds that promote axon regeneration. Here, we describe a growth cone collapse assay protocol used to study signal transduction mechanisms of the repulsive axon guidance molecule ephrin-A5 in hippocampal neurons.
    Full-text · Article · May 2013 · Methods in molecular biology (Clifton, N.J.)
  • Alexander I Son · Katie Sokolowski · Renping Zhou
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    ABSTRACT: Cryosectioning, the sectioning of frozen specimens, has been an important histological tool for more than a century and continues to be extensively utilized today. However, the ability to produce high-quality sections is often a difficult process requiring extensive patience and experience. In this chapter, we have detailed an effective method for the embedding, mounting, and sectioning of frozen tissues, as well as have provided suggestions in producing high-quality sections.
    No preview · Article · May 2013 · Methods in molecular biology (Clifton, N.J.)
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    ABSTRACT: The cells of the mammalian lens must be carefully organized and regulated to maintain clarity. Recent studies have identified the Eph receptor ligand ephrin-A5 as a major contributor to lens development, as mice lacking ephrin-A5 develop abnormal lenses, resulting in cataracts. As a follow-up to our previous study on the cataracts observed in ephrin-A5(-/-) animals, we have further examined the morphological and molecular changes in the ephrin-A5(-/-) lens. Wild-type and ephrin-A5(-/-) eyes at various ages were fixed, sectioned, and examined using histological techniques. Protein expression and localization were determined using immunohistochemistry and western blot analysis. Lens abnormalities in the ephrin-A5(-/-) animals are observed at postnatal stages, with lens opacity occurring by postnatal day 21. Structural defects in the lens are first observed in the outer lens fiber cell region where cells in the ephrin-A5(-/-) lens are severely disorganized. Ephrin-A5 and the Eph receptor EphA2 are expressed during early ocular development and continue to be expressed into postnatal stages. The cataracts in the ephrin-A5(-/-) mutants occur regardless of the presence of the CP49 mutation. In this follow-up study, we have uncovered additional details explicating the mechanisms underlying ephrin-A5 function in the lens. Furthermore, elucidation of the expression of ephrin-A5 and the Eph receptor EphA2 in the lens supports a fundamental role for this receptor-ligand complex in lens development. These observations, in concert with our previous study, strongly suggest that ephrin-A5 has a critical role in postnatal lens fiber organization to maintain lens transparency.
    Full-text · Article · Feb 2013 · Molecular vision
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    Jeong Eun Park · Alexander I Son · Rui Hua · Lianqing Wang · Xue Zhang · Renping Zhou
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    ABSTRACT: The cellular and molecular mechanisms underlying the pathogenesis of cataracts leading to visual impairment remain poorly understood. In recent studies, several mutations in the cytoplasmic sterile-α-motif (SAM) domain of human EPHA2 on chromosome 1p36 have been associated with hereditary cataracts in several families. Here, we have investigated how these SAM domain mutations affect EPHA2 activity. We showed that the SAM domain mutations dramatically destabilized the EPHA2 protein in a proteasome-dependent pathway, as evidenced by the increase of EPHA2 receptor levels in the presence of the proteasome inhibitor MG132. In addition, the expression of wild-type EPHA2 promoted the migration of the mouse lens epithelial αTN4-1 cells in the absence of ligand stimulation, whereas the mutants exhibited significantly reduced activity. In contrast, stimulation of EPHA2 with its ligand ephrin-A5 eradicates the enhancement of cell migration accompanied by Akt activation. Taken together, our studies suggest that the SAM domain of the EPHA2 protein plays critical roles in enhancing the stability of EPHA2 by modulating the proteasome-dependent process. Furthermore, activation of Akt switches EPHA2 from promoting to inhibiting cell migration upon ephrin-A5 binding. Our results provide the first report of multiple EPHA2 cataract mutations contributing to the destabilization of the receptor and causing the loss of cell migration activity.
    Full-text · Article · May 2012 · PLoS ONE
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    Alexander I Son · Jeong Eun Park · RenPing Zhou
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    ABSTRACT: Cataract is the single largest contributor to blindness in the world, with the disease having a strong genetic component. In recent years the Eph family of receptor tyrosine kinases has been identified as a key regulator in lens clarity. In this review we discuss the roles of the Eph receptors in lens biology and cataract development.
    Full-text · Article · May 2012 · Science China. Life sciences
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    ABSTRACT: Cell-cell interactions organize lens fiber cells into highly ordered structures to maintain transparency. However, signals regulating such interactions have not been well characterized. We report here that ephrin-A5, a ligand of the Eph receptor tyrosine kinases, plays a key role in lens fiber cell shape and cell-cell interactions. Lens fiber cells in mice lacking ephrin-A5 function appear rounded and irregular in cross-section, in contrast to their normal hexagonal appearance in WT lenses. Cataracts eventually develop in 87% of ephrin-A5 KO mice. We further demonstrate that ephrin-A5 interacts with the EphA2 receptor to regulate the adherens junction complex by enhancing recruitment of beta-catenin to N-cadherin. These results indicate that the Eph receptors and their ligands are critical regulators of lens development and maintenance.
    Full-text · Article · Nov 2008 · Proceedings of the National Academy of Sciences