LIF–IGF Axis Contributes to the Proliferation of Neural Progenitor Cells in Developing Rat Cerebrum

Abstract

In rodent models, leukemia inhibitory factor (LIF) is involved in cerebral development via the placenta, and maternal immune activation is linked to psychiatric disorders in the child. However, whether LIF acts directly on neural progenitor cells (NPCs) remains unclear. This study performed DNA microarray analysis and quantitative RT-PCR on the fetal cerebrum after maternal intraperitoneal or fetal intracerebral ventricular injection of LIF at day 14.5 (E14.5) and determined that the expression of insulin-like growth factors (IGF)-1 and -2 was induced by LIF. Physiological IGF-1 and IGF-2 levels in fetal cerebrospinal fluid (CSF) increased from E15.5 to E17.5, following the physiological surge of LIF levels in CSF at E15.5. Immunostaining showed that IGF-1 was expressed in the cerebrum at E15.5 to E19.5 and IGF-2 at E15.5 to E17.5 and that IGF-1 receptor and insulin receptor were co-expressed in NPCs. Further, LIF treatment enhanced cultured NPC proliferation, which was reduced by picropodophyllin, an IGF-1 receptor inhibitor, even under LIF supplementation. Our findings suggest that IGF expression and release from the NPCs of the fetal cerebrum in fetal CSF is induced by LIF, thus supporting the involvement of the LIF–IGF axis in cerebral cortical development in an autocrine/paracrine manner.

Prenatal Alcohol Exposure Impairs the Placenta–Cortex Transcriptomic Signature, Leading to Dysregulation of Angiogenic Pathways

“…between GO terms "vascular development" (3707) and the genic probes being under-expressed in cortex versus placenta only in the control signature (6), the genic probes under-expressed in cortex versus placenta only in the ethanol signature (14) and in both control and alcohol signatures (15). (B) Venn diagram showing the interaction between GO terms "vascular development" (3707) and the genic probes being over-expressed in cortex versus placenta only in the control signature (16), the genic probes over-expressed in cortex versus placenta only in the ethanol signature (43), and in both control and alcohol signatures (13). (C) Lists of genic probes resulting from the bioinformatic analysis, representing 107 proteins associated with vascular development.…”

“…(C) Lists of genic probes resulting from the bioinformatic analysis, representing 107 proteins associated with vascular development. A total of 22 proteins are under- (6) or over-( 16) expressed on cortex versus placenta only in the control signature, 57 proteins are under-( 14) or over- (43) expressed on the cortex versus placenta only in the alcohol signature and 28 proteins present in both signatures (common) are down (15) or up ( 13) dysregulated (+/− 40%) by alcohol exposure in the cortex versus placenta. (C) Among the 23 assigned proteins of the red-node cluster (28 proteins), 13 are regulators of transcriptional activity (dotted black line).…”

“…More recently, growing evidence supported a communication between the placenta and fetal brain, and neuroplacentology has emerged as a new field of research focusing on the role of the placenta in brain development [10][11][12][13]. As an example, a placenta-cortex axis involving the expression of LIF by trophoblasts and the resulting induction of cortical Igf has been shown to contribute to the proliferation of neural progenitors in the developing rat brain [43]. Interestingly, Igf1 was one of the ligands which appeared to be dysregulated by PAE in the present placenta-cortex signature.…”

Cellular and Molecular Mechanisms in Neurodevelopmental Disorders and Brain Tumors

“…Takata and colleagues [10] performed DNA microarray analysis and quantitative RT-PCR on the fetal cerebrum after maternal intraperitoneal or fetal intracerebral ventricular injection of leukemia inhibitory factor (LIF). Indeed, LIF is involved in cerebral development via the placenta in rat models, and maternal immune activity is connected to psychiatric problems in children.…”