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In this study we deleted the HtrA3 gene in the mouse and crossed females carrying zero, one, or two HtrA3-expressing alleles with HtrA3<jats:sup>+\/\u2212<\/jats:sup> males to investigate the role of maternal vs fetal HtrA3 in placentation. Although HtrA3<jats:sup>\u2212\/\u2212<\/jats:sup> mice were phenotypically normal and fertile, HtrA3 deletion in the mother resulted in intra-uterine growth restriction (IUGR). Disorganization of labyrinthine fetal capillaries was the major placental defect when HtrA3 was absent. The IUGR caused by maternal HtrA3 deletion, albeit being mild, significantly altered offspring growth trajectory long after birth. By 8 months of age, mice born to HtrA3-deficient mothers, independent of their own genotype, were significantly heavier and contained a larger mass of white fat. We further demonstrated that in women serum levels of HtrA3 during early pregnancy were significantly lower in IUGR pregnancies, establishing an association between lower HtrA3 levels and placental insufficiency in the human. This study thus revealed the importance of maternal HtrA3 in optimizing placental development and its long-term impact on the offspring well beyond <jats:italic>in utero<\/jats:italic> growth.<\/jats:p>","DOI":"10.1038\/s41598-017-04867-3","type":"journal-article","created":{"date-parts":[[2017,6,28]],"date-time":"2017-06-28T15:58:58Z","timestamp":1498665538000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Maternal HtrA3 optimizes placental development to influence offspring birth weight and subsequent white fat gain in adulthood"],"prefix":"10.1038","volume":"7","author":[{"given":"Ying","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lois A.","family":"Salamonsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Hyett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabricio da Silva","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiying","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,7,4]]},"reference":[{"key":"4867_CR1","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/S1097-2765(02)00658-5","volume":"10","author":"T Clausen","year":"2002","unstructured":"Clausen, T., Southan, C. & Ehrmann, M. The HtrA family of proteases. Implications for protein composition and cell fate. Mol Cell. \n                           10, 443\u2013455 (2002).","journal-title":"Mol Cell."},{"key":"4867_CR2","doi-asserted-by":"publisher","first-page":"2581","DOI":"10.1074\/jbc.275.4.2581","volume":"275","author":"L Faccio","year":"2000","unstructured":"Faccio, L. et al. Characterisation of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia. J Biol Chem. \n                           275, 2581\u20132588 (2000).","journal-title":"J Biol Chem."},{"key":"4867_CR3","doi-asserted-by":"publisher","first-page":"5699","DOI":"10.1046\/j.1432-1327.2000.01589.x","volume":"267","author":"CW Gray","year":"2000","unstructured":"Gray, C. W. et al. Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. 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