Biomedical subjects

Sherry T Hikita

Publications and source records attributed to Sherry T Hikita.

5 recordsLinked to original sources

PubMed2006

Osteopontin is proinflammatory in experimental autoimmune uveitis.

PURPOSE: Osteopontin (OPN) has been implicated in inflammatory and wound-healing processes. Increased OPN mRNA levels have been reported in experimental autoimmune uveitis (EAU), but the function of OPN in the inflamed eye is unknown. The purpose of this study was to investigate the role of OPN in the pathogenesis of EAU. METHODS: EAU was induced in OPN-null and wild-type (WT) mice by immunization with interphotoreceptor retinoid-binding protein (IRBP). Immunofluorescence experiments were performed to identify OPN-positive cells in WT mice. Disease incidence, serum IRBP antibody levels, vitreous infiltrates, retinal granulomas, and lymphocyte proliferation were assessed in OPN-null and WT mice. To determine whether OPN could induce an EAU-like condition, purified OPN and OPN fragments were injected intraocularly into WT mice and vitreous infiltrates were characterized and quantified. RESULTS: In WT EAU-positive eyes, cell types with increased OPN immunoreactivity were identified as F4/80-positive macrophages/microglia and CD4-positive T cells. OPN-null mice manifested attenuated disease with decreased vitreous infiltrates, fewer granulomas, less lymphocyte proliferation, and lower serum IRBP antibody levels. Exogenous full-length OPN, as well as N- and C-terminal fragments, induced leukocyte infiltration and retinal folding, with some similarities to EAU. CONCLUSIONS: The results demonstrate that OPN is proinflammatory in EAU and may be important for recruitment and activation of leukocytes in retinal inflammation.

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PubMed2005

Essential kinase-independent role of a Fer-like non-receptor tyrosine kinase in Caenorhabditis elegans morphogenesis.

Morphogenesis requires coordination of cell surface activity and cytoskeletal architecture. During the initial stage of morphogenesis in Caenorhabditis elegans, the concerted movement of surface epithelial cells results in enclosure of the embryo by the epidermis. We report that Fer-related kinase-1 (FRK-1), an ortholog of the mammalian non-receptor tyrosine kinase Fer, is necessary for embryonic enclosure and morphogenesis in C. elegans. Expression of FRK-1 in epidermal cells is sufficient to rescue a chromosomal deficiency that removes the frk-1 locus, demonstrating its autonomous requirement in the epidermis. The essential function of FRK-1 is independent of its kinase domain, suggesting a non-enzymatic role in morphogenesis. Localization of FRK-1 to the plasma membrane requires beta-catenin, but not cadherin or alpha-catenin, and muscle-expressed beta-integrin is non-autonomously required for this localization; in the absence of these components FRK-1 becomes nuclear. Mouse FerT rescues the morphogenetic defects of frk-1 mutants and expression of FRK-1 in mammalian cells results in loss of adhesion, implying a conserved function for FRK-1/FerT in cell adhesion and morphogenesis. Thus, FRK-1 performs a kinase-independent function in differentiation and morphogenesis of the C. elegans epidermis during embryogenesis.

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PubMed2004

Integrin alpha4beta1 function is required for cell survival in developing retina.

In the retina, integrins in the beta1 family have been shown to be important in many phases of neuronal development, particularly neuroblast migration and axon outgrowth. However, the functions of specific integrin heterodimers are not well defined. In this study, we investigated the functions of beta1 integrins in developing chicken retina by expression of a dominant-negative beta1A construct using a replication-competent retrovirus. Inhibition of integrins using this approach resulted in alteration of cell morphology and increased apoptosis, but did not preclude migration and axon elongation. In an attempt to identify which specific beta1 heterodimer was important, expression and function of the alpha4beta1 heterodimer were also investigated. At early developmental stages, alpha4 protein and mRNA were detected in undifferentiated neuroblasts throughout the retina. At later stages, expression was confined to retinal ganglion cells (RGCs) and amacrine cells. A small molecule antagonist of alpha4 integrins was shown to inhibit neurite outgrowth on recombinant soluble vascular cell adhesion molecule-1 (VCAM-1), a known ligand of alpha4beta1. Introduction of alpha4 antagonist in vivo gave rise to increased apoptosis and led to a thinning of the retina and reduced numbers of retinal ganglion cells (RGCs). We conclude that the integrin alpha4beta1 is important for survival of developing retinal neurons, including RGCs.

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PubMed2003

Integrins in the development, function and dysfunction of the nervous system.

Integrin receptors mediate cell-cell and cell-extracellular matrix (ECM) interactions in many different cell types, including neuronal cells. Earlier studies have shown a clear role for integrins in axon extension and cell adhesion/migration in CNS inflammation. Here we summarize more recent work that shows integrin functions in many phases of neural development, from neuroblast migration to synapse formation. Integrins of the beta-1 and alpha-v family are widely expressed on neurons at many stages of development, and their activity is regulated. Integrins are also important in the adult nervous system, since they have been implicated in synaptic plasticity involved in memory and learning. In addition, several diseases of the nervous system appear to involve beta-1, beta-2, and alpha-v integrins on leukocytes and glial cells. Research challenges for the future include understanding functions of specific integrin heterodimers and identifying the relevant integrin ligands that function in the nervous system.

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PubMed2003

Integrin alpha4beta1 (VLA-4) expression and activity in retinal and peripheral neurons.

The integrin alpha4beta1 fulfills important roles in inflammation and hematopoesis, but its functions in neurons are not well understood. Here we show that the alpha4 subunit is expressed on mouse retinal ganglion cells (RGCs) and undifferentiated retinal neuroblasts during the period of axon extension and migration. To determine if alpha4 integrins expressed by retinal neurons were active, neurons were cultured on known alpha4 ligands in vitro. Recombinant soluble vascular cell adhesion molecule 1 (rsVCAM-1), fibronectin, and osteopontin (OPN) induced neurite outgrowth that was diminished by function blocking antibodies specific for alpha4. Neurite outgrowth on OPN was also blocked by antibodies to the integrin beta1 subunit, implicating the alpha4beta1 heterodimer as one integrin receptor mediating outgrowth on OPN. OPN immunoreactivity was detected in the RGC fiber layer and optic nerve, suggesting that it may act as an alpha4 ligand in vivo. Neurons from chick lumbar sympathetic ganglia, chick dorsal root ganglia, and mouse superior cervical ganglia also extended neurites on rsVCAM-1, suggesting that integrin alpha4beta1 may play a role in the development of multiple neuronal cell types.

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