SDC4
Syndecan-4 precursor (SYND4) (Amphiglycan) (Ryudocan core protein)
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To determine the impact of the loss of syndecan 1 (SDC1) on intraepithelial corneal nerves (ICNs) during homeostasis, aging, and in response to 1.5-mm trephine and debridement injury. Whole-mount corneas are used to quantify ICN density and thickness over time after birth and in response to injury in SDC1-null and wild-type (WT) mice. High-resolution three-dimensional imaging is used to visualize intraepithelial nerve terminals (INTs), axon fragments, and lysosomes in corneal epithelial cells using antibodies against growth associated protein 43 (GAP43), βIII tubulin, and LAMP1. Quantitative PCR was performed to quantify expression of SDC1, SDC2, SDC3, and SDC4 in corneal epithelial mRNA. Phagocytosis was assessed by quantifying internalization of fluorescently labeled 1-μm latex beads. Intraepithelial corneal nerves innervate the corneas of SDC1-null mice more slowly. At 8 weeks, ICN density is less but thickness is greater. Apically projecting intraepithelial nerve terminals and lysosome-associated membrane glycoprotein 1 (LAMP1) are also reduced in unwounded SDC1-null corneas. Quantitative PCR and immunofluorescence studies show that SDC3 expression and localization are increased in SDC1-null ICNs. Wild-type and SDC1-null corneas lose ICN density and thickness as they age. Recovery of axon density and thickness after trephine but not debridement wounds is slower in SDC1-null corneas compared with WT. Experiments assessing phagocytosis show reduced bead internalization by SDC1-null epithelial cells. Syndecan-1 deficiency alters ICN morphology and homeostasis during aging, reduces epithelial phagocytosis, and impairs reinnervation after trephine but not debridement injury. These data provide insight into the mechanisms used by sensory nerves to reinnervate after injury.
MeSH Terms
- Aging
- Animals
- Axons
- Cornea
- Corneal Injuries
- Disease Models, Animal
- Epithelium, Corneal
- Homeostasis
- Mice
- Mice, Inbred BALB C
- Nerve Fibers
- Syndecan-1
- Syndecans
Evidences from model systems and humans have suggested that genetic alterations in cell-ECM interactions and matrix-mediated cellular signaling cascades impact different aspects of metabolism and thereby life span. In this frame, a genetic variant (rs1981429) in the SDC4 gene encoding for syndecan-4, a central mediator of cell adhesion, has been associated with body composition in children and coronary artery disease in middle-age subjects. In order to test the hypothesis that syndecans might affect life span by affecting metabolic endophenotypes, 11 SNPs within the SDC4 gene were tested for association with longevity in a cohort of 64-107 aged individuals. We then determined whether the longevity-associated SNPs were correlated with metabolic parameters in the age group 64-85 years. RobustSNP association tests showed that rs1981429 was negatively associated with longevity (Theop=0.028), but also with high levels of triglyceride (Theop=0.028) and low levels of low-density lipoprotein-cholesterol (LDL-C) (Theop=0.009). On the other hand, rs2251252 was found to be positively correlated with longevity (Theop=0.018) and high LDL-C (Theop=0.022). On the whole, our results suggest that SDC4 alleles affect lipid profile in elderly subjects and may in part mediate the link between LDL-C and longevity.
MeSH Terms
- Aged
- Aged, 80 and over
- Cholesterol, LDL
- Female
- Humans
- Italy
- Longevity
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Syndecan-4
- Triglycerides
Keywords
- Aging
- Extracellular matrix
- Longevity
- Metabolism
- Syndecans