High Temperature Requirement Factor A1 (HTRA1) Gene Regulates Angiogenesis through Transforming Growth Factor-β Family Member Growth Differentiation Factor 6

Abstract

Background: Genetic variants of high temperature requirement factor A1 (HTRA1) associate with AMD risk. Results: Growth differentiation factor 6 (GDF6) gene polymorphism significantly associated with AMD. HTRA1 knock-out mice display reduced blood vessel in retina and up-regulation of GDF6. Conclusion: HTRA1 regulates angiogenesis via TGF-␤ signaling by GDF6, a novel disease gene. Significance: This novel pathway of HTRA1 in regulation of vascularization is critical for understanding AMD pathogenesis.

Glomerular Cell Cross-Talk Influences Composition and Assembly of Extracellular Matrix

“…For example, components, such as collagen VI and TINAGL1, were enriched in coculture and glomerular ECM, whereas the expression of other components was reduced compared with monoculture ECM. Interestingly, proteins associated with vascular development, such as CYR61 23 and HRTA1, 26 were downregulated in coculture ECM compared with GEnC ECM. This finding suggests that paracrine factors may influence cell differentiation and fate.…”

HtrA1 Is a Novel Antagonist Controlling Fibroblast Growth Factor (FGF) Signaling via Cleavage of FGF8

“…Several cellular and molecular studies have suggested that HtrA1 serves as a key player in regulating various cellular processes through cleavage of and/or binding to pivotal factors that participate in cell proliferation, migration, and fate (8,9). Moreover, dysregulation of HtrA1 expression or its serine protease activity has been implicated in the pathogenesis of important diseases, such as cancer (1,(6)(7)(8)23), arthritis (19), age-related macular degeneration (AMD) (11,14,27,46,48), and neuropathological disorders (18,22,41). The physiological functions of HtrA1 in vivo, however, remain largely unknown.…”

HTRA1 (High Temperature Requirement A Serine Peptidase 1) Gene Is Transcriptionally Regulated by Insertion/Deletion Nucleotides Located at the 3′ End of the ARMS2 (Age-related Maculopathy Susceptibility 2) Gene in Patients with Age-related Macular Degeneration

“…Immunohistochemistry-Eyes from wild type, HtrA1 knockout, and HtrA1 transgenic mice (12,16,23) were resected and immersed in a fixative containing 4% paraformaldehyde overnight at 4°C. The eyes were embedded in OCT compound and frozen on dry ice.…”

“…HTRA1 belongs to the HTRA serine protease family, which is highly conserved from microorganisms to multicellular organisms, including humans (11). Several cellular and molecular studies have suggested that HTRA1 plays a key role in regulating various cellular processes via the cleavage and/or binding of pivotal factors that participate in cell proliferation, migration, and cell fate (12)(13)(14)(15). Recently, up-regulation of human HTRA1 expression in the mouse retinal pigment epithelium (RPE) was shown to induce a branching network of choroidal vessels and polypoidal lesions and severe degeneration of the elastic lamina and tunica media of the choroidal vessels, similar to that observed in AMD and PCV patients (16,17).…”