Lokeshwar S. Bhenderu

Introduction: Fetal alcohol spectrum disorder (FASD) is an umbrella term to describe the continuum of disorders due to prenatal alcohol exposure (PAE)^1,2. Estimates show that FASD affects 1.1 to 4.8% of school-aged children in the United States¹. FASD leads to a range of clinical presentations from craniofacial dysmorphologies to neurodevelopmental disorders¹. Despite the relatively wide-spread prevalence and significant downstream effects, the pathogenesis of FASD is not thoroughly understood². Recently, the role of microRNAs in the development of FASD has been brought to focus because various studies have shown that alcohol alters microRNA expression³. MiR-153 is of specific interest because it targets nuclear factor I A/B (NFIA/B), which are key transcription factors that regulate the initiation of gliogenesis⁴. Since NFIA/B control the ability of neural stem cells to differentiate into glial cells and miR-153 affects NFIA/B expression, understanding the role of PAE in the relationship between miR-153 and NFIA/B is important in order to elucidate the pathogenesis of FASD. Methods: Animal experiments for PAE were performed using mice. NFIA/B experiments were performed using NFIA/NFIB deficient mice, and PAE experiments were performed by administering ethanol by either oral intubation or intragastric injection. Cross sections and neurospheres were analyzed using either chromogenic or fluorescence immunochemistry. Results: NFIA/B were shown to affect gliogenesis through regulating the expression of nuclear factor I X (NFIX). Spinal cord cross-sections that were NFIA or NFIB deficient both showed a reduction in NFIX expression⁵. MiR-153 was shown to play an important role in the interaction between NFIA/B and NFIX because neural stem cells that were exposed to miR-153 showed a significant reduction in the number of glial cells⁴. Experiments showed that maternal binge alcohol consumption led to an increase in NFIA expression and there was a significant reduction in miR-153 following PAE^6,7. These results are consistent because if PAE leads to a reduction of miR-153, then the inhibition of NFIA expression by miR-153 will be reduced. A potential therapeutic was found with choline supplementation because rats administered choline after alcohol exposure showed miRNA expression toward control levels⁸. Conclusions: These results show that PAE leads to a reduced expression of miR-153. This reduction of miR-153 levels increases expression of NFIA/B and leads to gliogenesis. These studies begin to elucidate the mechanistic role by which PAE leads to downstream developmental abnormalities found in FASD because PAE can alter the normal levels of miR-153 and lead to erroneous gliogenesis.

1. Garrison, Laura, et al. “Forty Years of Assessing Neurodevelopmental and Behavioral Effects of Prenatal Alcohol Exposure in Infants: What Have We Learned?”Alcoholism: Clinical and  Experimental  Research,    43,  no.  8,  Mar.  2019,  pp.  1632–1642., doi:10.1111/acer.14127.
2. Ehrhart, Friederike, et al. “Reviewand Gap Analysis: Molecular Pathways Leading to Fetal Alcohol Spectrum Disorders.”Molecular Psychiatry,    24,  no.  1,  Nov.  2018, pp. 10–17., doi:10.1038/s41380-018-0095-4.
3. Rocco, Giuliana Di, et al. “Stem Cells under the Influence of Alcohol: Effects of Ethanol Consumption on Stem/Progenitor Cells.”Cellular and  Molecular  Life  Sciences,  76, no. 2, Oct. 2018, pp. 231–244., doi:10.1007/s00018-018-2931-8.
4. Tsuyama, J., Bunt, J., Richards, L. J., Iwanari, H., Mochizuki, Y., Hamakubo, T., … Okano, H. (2015). MicroRNA-153 Regulates the Acquisition of Gliogenic Competence by Neural Stem Cells.Stem Cell Reports,5(3), 365–377. doi: 10.1016/j.stemcr.2015.06.006
5. Matuzelski, E., Bunt, J., Harkins, D., Lim, J. W., Gronostajski, R. M., Richards, L. J., … Piper,    (2017).  Transcriptional  regulation  of  Nfix  by  NFIB  drives  astrocytic maturation  within  the  developing  spinal  cord.Developmental  Biology,432(2),  286–297. doi: 10.1016/j.ydbio.2017.10.019
6. Mandal, C., Park, J. H., Lee, H. T., Seo, H., Chung, I. Y., Choi, I. G., … Chai, Y. G. (2015). Reduction  of  Nfia  gene  expression  and  subsequent  target  genes  by  binge alcohol in the fetal brain.Neuroscience Letters,598, 73–78. doi: 10.1016/j.neulet.2015.05.016
7. Balaraman, S., Schafer, J. J., Tseng, A. M., Wertelecki, W., Yevtushok, L., Zymak-Zakutnya, N., … Miranda, R. C. (2016). Plasma miRNA Profiles in Pregnant Women Predict Infant Outcomes following Prenatal Alcohol Exposure.Plos One,11(11). doi: 10.1371/journal.pone.0165081
8. Balaraman, S., Idrus, N. M., Miranda, R. C., & Thomas, J. D. (2017). Postnatal choline supplementation selectively attenuates    hippocampal    microRNA    alterations associated   with   developmental   alcohol   Alcohol,60,   159–167.   doi: 10.1016/j.alcohol.2016.12.006