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HtrA3 in placental development and pregnancy disorders
Summary
We have discovered and cloned a new gene, HtrA3, in the mouse and human, and identified that it is a previously unrecognised factor important for placental development and function. We are investigating the molecular mechanisms of HtrA3 action during placentation, and the contribution of HtrA3 dysregulation in pregnancy disorders such as pre-eclampsia and intra-uterine growth restrictions.
Description
HtrA3 is a new member of the mammalian HtrA family. The first member of HtrA (high temperature requirement factor A) was identified in E.coli as a heat shock protein required for high temperature tolerance. Subsequently, 4 mammalian HtrA3 proteins have been identified with a range of cellular functions such as in apoptosis and cancer.
We discovered and cloned HtrA3 both in the mouse and human, and established that it is closely associated with placental development.
We are currently investigating the importance of HtrA3 in placental development and function using genetically modified mouse models. Our data suggest that HtrA3 is critical for normal placental development and the growth of the foetus in utero. Dysregulation of HtrA3 leads to intra-uterine growth restriction and low-birth weight babies with long-term adverse health consequences.
We are also investigating the expression and function of HtrA3 in human placentation using a number of approaches including cell culture, transfection, siRNA knockdown, proteomics and molecular biology approaches. In addition, we are establishing the link between HtrA3 dysregulation and pregnancy disorders such as pre-eclampsia and intra-uterine growth restriction in women.
Funding
National Health and Medical Research Council
Outcomes
We have established that HtrA3 is critical for placental development and function
In these studies dysregulation of HtrA3 is linked to pregnancy disorders
Selected Publication
Li Y, Puryer M, Lin E, Hale K, Salamonsen LA, Manuelpillai U, Tong S, Chan W, Wallace EM and Nie G (2010) Placental HtrA3 is regulated by oxygen tension and serum levels are altered during early pregnancy in women destined to develop preeclampsia. J. Clin. Endocrinol. Metab. 96, 403-411
Singh H, Makino S-I, Endo Y and Nie G (2010) Inhibition of HTRA3 stimulates trophoblast invasion during human placental development. Placenta, 31, 1085-1092
Singh H, Endo Y, Nie G. Decidual HtrA3 negatively regulates trophoblast invasion during human placentation. Human Reprod [accepted in Jan 2010].
Bowden MA, Drummond AE, Salamonsen LA, Findlay JK, and Nie G (2009) Evolutionary conservation of mammalian HtrA3 and its developmental regulation in the rat ovary. J. Exp. Zool. Part B 312, 701-13.
Nie G. The critical role of a novel protease in normal and abnormal placentation. Biol Reprod 2008; 78: p275
Bowden MA, Li Y, Findlay JK, Salamonsen LA and Nie G (2008) HtrA3 expression in non-pregnant rhesus monkey ovary, endometrium and at the maternal-fetal interface during early pregnancy. Reprod Biol Endocrinol 6 (22), 1-11.
Than NG, Romero R, Hillermann R, Cozzi V, Nie G, Huppertz B (2008) Prediction of Pre-eclampsia. Placenta 29, Suppl 1:S83-85.
Bowden MA, Di Nezza-Cossens LA, Jobling T, Salamonsen LA and Nie G (2006) Serine proteases HtrA1 and HtrA3 are down-regulated with increasing grades of human endometrial cancer. Gynecol Oncol 103, 253-260.
Nie G, Hale K, Li Y, Manuelpillai U, Wallace EM and Salamonsen LA (2006). Distinct expression and localization of serine protease HtrA1 in human endometrium and first-trimester placenta. Dev Dyn 235, 3448-3445.
Nie G, Li Y and Salamonsen LA (2005). Serine protease HtrA1 is developmentally regulated in trophoblast and uterine decidual cells during placental formation in the mouse. Dev Dyn 233, 1102-1109.
Nie G, Li Y, He H, Findlay JK and Salamonsen LA (2006). Serine protease HtrA3 possessing an IGF binding domain is specifically expressed in the maternal-fetal interface during placentation in the mouse. Placenta 27: 491-501.
Nie G, Li Y, Hale K, Okada H, Manuelpillai U, Wallace EM and Salamonsen LA (2006). Serine peptidase HtrA3 is closely associated with human placental development and elevated in pregnancy serum. Biol Reprod 74, 366-374.
Nie G, Hampton A, Li Y, Findlay JK, Salamonsen LA (2003) Identification and cloning of two isoforms of human HtrA3, characterisation of its genomic structure and comparison of its tissue distribution with HtrA1 and HtrA2. Biochem J 371, 39-48.
Nie G, Li Y, Minoura H, Batten L, Ooi GT, Findlay JK and Salamonsen LA (2003) A novel serine protease of the mammalian HtrA family is dramatically up-regulated in mouse uterus coinciding with placentation. Mol Hum Reprod 9, 279-290