Novel roles of mechanistic target of rapamycin signaling in regulating fetal growth

• Published in: Biology of reproduction 2019-04, Vol.100 (4), p.872-884
• Main Authors: Gupta, Madhulika B, Jansson, Thomas
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Bioavailability; Biological research; Cellular signal transduction; decidua; developmental origins of health and disease; Female; Fetal development; Fetal Development - genetics; Fetal Growth Retardation - genetics; Fetal Growth Retardation - metabolism; Fetal Macrosomia - genetics; Fetal Macrosomia - metabolism; Folic acid; Glucose; Growth hormones; Hormones; Humans; Insulin; insulin-like growth factor; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factors; intrauterine growth restriction; kinases; Liver; metabolism; Novels; Nutrition; Phosphorylation; Phosphotransferases; Physical growth; Physiological aspects; placenta; Placenta - metabolism; placental transport; Pregnancy; Prenatal development; Protein binding; Protein synthesis; Reproductive health; REVIEW; Signal Transduction - genetics; Somatotropin; syncytiotrophoblast; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - physiology
• ISSN: 0006-3363; 1529-7268; 1529-7268
• DOI: 10.1093/biolre/ioy249

Mechanistic target of rapamycin (mTOR) signaling functions as a central regulator of cellular metabolism, growth, and survival in response to hormones, growth factors, nutrients, energy, and stress signals. Mechanistic TOR is therefore critical for the growth of most fetal organs, and global mTOR deletion is embryonic lethal. This review discusses emerging evidence suggesting that mTOR signaling also has a role as a critical hub in the overall homeostatic control of fetal growth, adjusting the fetal growth trajectory according to the ability of the maternal supply line to support fetal growth. In the fetus, liver mTOR governs the secretion and phosphorylation of insulin-like growth factor binding protein 1 (IGFBP-1) thereby controlling the bioavailability of insulin-like growth factors (IGF-I and IGF-II), which function as important growth hormones during fetal life. In the placenta, mTOR responds to a large number of growth-related signals, including amino acids, glucose, oxygen, folate, and growth factors, to regulate trophoblast mitochondrial respiration, nutrient transport, and protein synthesis, thereby influencing fetal growth. In the maternal compartment, mTOR is an integral part of a decidual nutrient sensor which links oxygen and nutrient availability to the phosphorylation of IGFBP-1 with preferential effects on the bioavailability of IGF-I in the maternal–fetal interface and in the maternal circulation. These new roles of mTOR signaling in the regulation fetal growth will help us better understand the molecular underpinnings of abnormal fetal growth, such as intrauterine growth restriction and fetal overgrowth, and may represent novel avenues for diagnostics and intervention in important pregnancy complications. Summary Sentence Emerging evidence suggest that mTOR signaling in the fetal liver, trophoblast, and decidua serves as a critical hub in the overall homeostatic control of fetal growth, adjusting the fetal growth trajectory according to the ability of the maternal supply line to support fetal growth.