Transient Maternal IL-6 Mediates Long-Lasting Changes in Neural Stem Cell Pools by Deregulating an Endogenous Self-Renewal Pathway

• A single maternal injection of IL-6 causes an expansion of the adult NSC pool
• An expanded NSC pool is a result of enhanced self-renewal of embryonic precursors
• Maternal IL-6 acts on an endogenous IL-6 self-renewal pathway
• Maternal cytokine flares during embryogenesis can impact brain development long term

SummaryThe mechanisms that regulate the establishment of adult stem cell pools during normal and perturbed mammalian development are still largely unknown. Here, we asked whether a maternal cytokine surge, which occurs during human maternal infections and has been implicated in cognitive disorders, might have long-lasting consequences for neural stem cell pools in adult progeny. We show that transient, maternally administered interleukin-6 (IL-6) resulted in an expanded adult forebrain neural precursor pool and perturbed olfactory neurogenesis in offspring months after fetal exposure. This increase is likely the long-term consequence of acute hyperactivation of an endogenous autocrine/paracrine IL-6-dependent self-renewal pathway that normally regulates the number of forebrain neural precursors. These studies therefore identify an IL-6-dependent neural stem cell self-renewal pathway in vivo, and support a model in which transiently increased maternal cytokines can act through this pathway in offspring to deregulate neural precursor biology from embryogenesis throughout life.