Maternal Leukemia Inhibitory Factor (LIF) Promotes Fetal Neurogenesis via a LIF-ACTH-LIF Signaling Relay Pathway

• Published in: Endocrinology (Philadelphia) 2010-04, Vol.151 (4), p.1853-1862
• Main Authors: Simamura, Eriko, Shimada, Hiroki, Higashi, Nobuaki, Uchishiba, Maimi, Otani, Hiroki, Hatta, Toshihisa
• Format: Article
• Language: English
• Subjects: Adrenal Glands - metabolism; Adrenocorticotropic hormone; Adrenocorticotropic Hormone - genetics; Adrenocorticotropic Hormone - metabolism; Age Factors; Analysis of Variance; Animals; Biological and medical sciences; Cell Line; Cell proliferation; Cells, Cultured; Cerebral cortex; Cerebrospinal fluid; Cerebrum; Cytokine Receptor gp130 - genetics; Cytokine Receptor gp130 - metabolism; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Erythrocytes - metabolism; Female; Fetuses; Fundamental and applied biological sciences. Psychology; Glycoproteins; Hypothalamo-Hypophyseal System - metabolism; Immunohistochemistry; Injection; Leukemia; Leukemia inhibitory factor; Leukemia Inhibitory Factor - genetics; Leukemia Inhibitory Factor - metabolism; Maternal-Fetal Exchange - physiology; Neocortex; Neural stem cells; Neurogenesis; Neurogenesis - physiology; Pituitary Gland - metabolism; Pituitary-Adrenal System - metabolism; Placenta; Placenta - metabolism; Pregnancy; Pro-Opiomelanocortin - genetics; Pro-Opiomelanocortin - metabolism; Progenitor cells; Rats; Rats, Wistar; Receptors, OSM-LIF - genetics; Receptors, OSM-LIF - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - physiology; Time Factors; Trophoblasts - metabolism; Ventricular zone; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2009-0985

Leukemia inhibitory factor (LIF) promotes the proliferation of neuronal progenitor cells in the cerebrum. However, it remains unclear how fetal LIF level is regulated. Here we show evidence that maternal LIF signals drive fetal LIF levels via the placenta, thereby promoting neurogenesis in the fetal brain in rats. Chronological changes showed that LIF concentration in fetal sera (FS) and fetal cerebrospinal fluid peaked at gestational day (GD) 15.5, after the peak of maternal LIF at GD14.5. LIF injection into rat dams at GD15.5 increased the level of ACTH in FS and subsequently increased LIF levels in FS and fetal cerebrospinal fluid. The elevation of fetal LIF after LIF injection into dams was inhibited by in utero injection of anti-ACTH antibody into fetuses. Cultured syncytiotrophoblasts, which express the LIF receptor and glycoprotein 130, were induced to secrete ACTH and up-regulate Pomc expression by the addition of LIF. Nucleated red blood cells from fetuses at GD15.5, but not GD13.5 or GD17.5, displayed LIF secretion in response to ACTH. Moreover, injection of LIF into dams at GD13.5 or GD17.5 did not result in elevation of ACTH or LIF in fetuses. The labeling index of 5-bromo-2′-deoxyuridine-positive cells in the ventricular zone of the cerebral neocortex increased 24 h after injection of LIF into dams at GD15.5 but not GD13.5 or GD17.5. These results suggest that in rats maternal LIF induces ACTH from the placenta, which in turn induces fetal nucleated red blood cells to secrete LIF that finally increases neurogenesis in fetuses around GD15. Maternal leukemia inhibitory factor (LIF) induces ACTH from the placenta, which in turn induces LIF secretion from fetal red blood cells; LIF then increases neurogenesis in the rat fetus.