title: HtrA1 is a novel antagonist controlling fibroblast growth factor (FGF) signaling via cleavage of FGF8.
abstract: Accumulating evidence suggests that HtrA1 (high-temperature requirement A1) is involved in modulating crucial cellular processes and implicated in life-threatening diseases, such as cancer and neuropathological disorders; however, the exact functions of this protease in vivo remain unknown. Here, we show that loss of HtrA1 function increases fibroblast growth factor 8 (FGF8) mRNA levels and triggers activation of FGF signaling, resulting in dorsalization in zebrafish embryos. Notably, HtrA1 directly cleaves FGF8 in the extracellular region, and this cleavage results in decreased activation of FGF signaling, which is essential for many physiological processes. Therefore, HtrA1 is indispensable for dorsoventral patterning in early zebrafish embryogenesis and serves as a key upstream regulator of FGF signaling through the control of FGF levels. Furthermore, this study offers insight into new strategies to control human diseases associated with HtrA1 and FGF signaling.
authors.affiliation: Department of Medical Life Sciences, College of Medicine, Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Goo-Young
authors.initials: GY
authors.lastname: Kim
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Hyun-Taek
authors.initials: HT
authors.lastname: Kim
authors.forename: Jeong-Mi
authors.initials: JM
authors.lastname: Moon
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Kim
authors.forename: Seongman
authors.initials: S
authors.lastname: Kang
authors.forename: Hyangshuk
authors.initials: H
authors.lastname: Rhim
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D000074289:High-Temperature Requirement A Serine Peptidase 1; D060172:Morpholinos / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D060172:Morpholinos; D012333:RNA, Messenger; D029961:Zebrafish Proteins; D051524:Fibroblast Growth Factor 8; D000074289:High-Temperature Requirement A Serine Peptidase 1; C577319:HtrA1A protein, zebrafish; D012697:Serine Endopeptidases