Impaired female fertility in tubulointerstitial antigen-like 1-deficient mice

Abstract

Tubulointerstitial nephritis antigen-like 1 (Tinagl1, also known as adrenocortical zonation factor 1 [AZ-1] or lipocalin 7) is a matricellular protein. Previously, we demonstrated that Tinagl1 expression was restricted to extraembryonic regions during the postimplantation period and detected marked expression in mouse Reichert’s membranes. In uteri, Tinagl1 is markedly expressed in the decidual endometrium during the postimplantation period, suggesting that it plays a physical and physiological role in embryo development and/or decidualization of the uterine endometrium during pregnancy. In the present study, in order to determine the role of Tinagl1 during embryonic development and pregnancy, we generated Tinagl1-deficient mice. Although Tinagl1–/– embryos were not lethal during development to term, homologous matings of Tinagl1–/– females and Tinagl1–/– males showed impaired fertility during pregnancy, including failure to carry pregnancy to term and perinatal lethality. To examine ovarian function, ovulation was induced with equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG); the number of ovulated oocytes did not differ between Tinagl1–/– and Tinagl1flox/flox. In vitro fertilization followed by embryo culture also demonstrated the normal developmental potential of Tinagl1-null embryos during the preimplantation period. Our results demonstrate that Tinagl1 deficiency affects female mice and results in subfertility phenotypes, and they suggest that although the potential of Tinagl1–/– oocytes is normal, Tinagl1 is related to fertility in adult females but is not essential for either fertilization or preimplantation development in vitro.

Mass spectrometry‐based secretome analysis of non‐small cell lung cancer cell lines

“…Tubulointerstitial nephritis antigen‐like 1, also known as adrenocortal zonation factor 1 or lipocalin 7, interacts with structural matrix proteins as well as cell surface receptors and promotes cell adhesion and spreading . It is a component of the basal lamina and Reichert membrane, which is known for its role in reproduction . Furthermore, it is a potential target to suppress metastasis in NSCLC and other cancer types .…”

Acute knockdown of extracellular matrix protein Tinagl1 disrupts heart laterality and pronephric cilia in zebrafish embryonic development

“…Furthermore, Tinagl1 has shown direct physical associations with Wnts, apparently increasing their activity and stability after secretion (Mulligan et al, 2012), and with the FN-binding integrin receptor and with EGF-R, blocking binding of FN and dimerization of EGF-R respectively (Shen et al, 2019). Despite these intriguing functional studies, a tinagl1 knockout mouse line is viable and fertile and can be maintained over numerous generations (Takahashi et al, 2016), suggesting the protein is dispensable for mouse survival at least under un-challenged laboratory conditions. A tinag knockout mouse has not been described.…”

“…These include genetic compensation by tinag or other ECM/signaling proteins when tinagl1 expression is chronically abrogated in the knockout mouse (Rossi et al, 2015) and, for comparisons of whole animal work, examining post-natal versus embryonic roles. Notably, the knockout mouse line has fetal losses across pregnancy, though these were not characterized and were attributed to insufficiency of the placenta, a vascular tissue in which Tinagl1 is expressed (Tajiri et al, 2010;Takahashi et al, 2016). The single reported mouse developmental study, in which the kidney-enriched ortholog, Tinag, was acutely knocked down in mouse embryonic kidney explants, did show severe disruption of renal tubulogenesis and ureteric bud branching (Kanwar et al, 1999), suggesting either a critical role just for Tinag or that acute knockdown does not allow time for functional compensation by Tinagl1.…”

“…Inhibition of Tinag expression in a mouse embryonic kidney explant model reduced tubulogenesis and ureteric branching morphogenesis, while glomerular differentiation was preserved (Kanwar et al, 1999). A Tinagl1 knockout mouse is viable without gross phenotypes, but has impaired female fertility with fetal losses across gestation (Takahashi et al, 2016). Although the investigators postulated that the placenta, normally enriched in Tinagl1 (Tajiri et al, 2010), is defective, the fetal defects were not explored.…”

Molecular and cellular events during blastocyst implantation in the receptive uterus: clues from mouse models

“…These findings suggest that it plays a physical and physiological role in embryo development and/or decidualization of the uterine endometrium during pregnancy. Indeed, TINAGL1 deficiency affects female mice and results in subfertility phenotypes [ 72 ]. In humans, TINAGL1 protein is downregulated in preeclamptic women [ 73 ].…”