Editors' ChoiceDevelopment

From maternal infection to aberrant fetal brain development

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Science Signaling  15 Mar 2016:
Vol. 9, Issue 419, pp. ec57
DOI: 10.1126/scisignal.aaf6684

Getting a bacterial infection or having abnormal metabolism, such as diabetes, during pregnancy can be dangerous to the baby. Humann et al. found that a bacterial peptidoglycan of the cell wall (CW) of Gram-positive bacteria crossed the placenta and stimulated proliferation of neurons in the developing fetal brain. Less fluorescently labeled CW accumulated in the brains of fetal mice deficient in platelet-activating factor receptor (PAFR). In infants, children, and adults, meningitis—the disease caused by bacterial infection with these types of bacteria in the brain—causes neuronal cell death, and this same response occurs in mice infected with the relevant bacteria or injected with CW. In contrast, the embryonic mice exhibited an increase in neuronal density and immature neuronal proliferation when the mothers were injected with CW, and both responses were absent in PAFR-deficient mice or in mice lacking the Toll-like receptor TLR2. Analysis of CW accumulation in the embryos or the response of neuronal precursor cells in culture to CW indicated that PAFR was required for CW to accumulate in the embryos, whereas both receptors were involved in the proliferation response. Injection of pregnant mice with CW resulted in an increase in the abundance of the neuronal transcription factor FoxG1 (a member of the Forkhead family of transcription factors) in the developing brain, a response dependent on PAFR and TLR2. Infected pregnant mice treated with the antibiotic ampicillin, an antibiotic that triggers release of CW, but not with clindamycin, an antibiotic that inhibits bacterial protein synthesis, induced the increase in neuronal density in the brains of the embryos. Similar results were obtained with antibiotic-treated pneumococci added to neuronal precursor cells in culture; only the ampicillin-treated bacteria induced proliferation. Analysis of mice born to mothers injected with CW when the embryos were at day 10 or day 15 showed that only those exposed at day 10 exhibited memory and cognition defects. These data show that PAFR and TLR2 play an important role in the regulation of neuronal proliferation and indicate that antibiotic treatment of pregnant women needs to be evaluated for potential toxic effects resulting from their mechanism of controlling the bacterial infection.

Research published in Science Signaling identified another pathway involving a different member of the Forkhead family, FoxO3a, in neural tube defects that arise from maternal hyperglycemia. In this case, the response is not aberrant proliferation, but apoptosis, initiated by hyperglycemia-induced activation of the apoptosis signal–regulated kinase 1 (ASK1) in the developing neural tube. By studying the effect of hyperglycemia in pregnant mice on the developing embryos, Yang et al. found that the activity of ASK1 increased in the developing neural tube, which stimulated FoxO3a activity, resulting in an increase in the expression of the gene encoding the apoptosis-promoting adaptor protein TRADD and consequently activation of caspase 8 and neuronal apoptosis. This pathway is relevant in humans; the abundance or activation of its components was detected in neural tissue exhibiting neural tube defects. Thus, either aberrant proliferation or apoptosis in the developing embryo can involve transcription factors from the same family and produce neurological defects.

J. Humann, B. Mann, G. Gao, P. Moresco, J. Ramahi, L. N. Loh, A. Farr, Y. Hu, K. Durick-Eder, S. A. Fillon, R. J. Smeyne, E. I. Tuomanen, Bacterial peptidoglycan transverses the placenta to induce fetal neuroproliferation and aberrant postnatal behavior. Cell Host Microbe 19, 388­–399 (2016). [PubMed]

P. Yang, X. Li, C. Xu, R. L. Eckert, E. A. Reece, H. R. Zielke, F. Wang, Maternal hyperglycemia activates an ASK1–FoxO3a–Caspase 8 pathway that leads to embryonic neural tube defects. Sci. Signal. 6, ra74 (2013). [Abstract]

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