The Developmental Neurobiology laboratory
at Children's Memorial Research Center and the Division of Neurosurgery at Children’s Memorial Hospital are investigating the mechanisms that cause neural tube defects.
An estimated 3,000 pregnancies in the U.S. are affected by neural tube defects annually. Research shows that if all women who could become pregnant consumed recommend amounts of folic acid (FA) before and during pregnancy, the risks of neural tube defects such spina bifida could be decreased by 70 percent. Currently, the mechanisms behind FA rescue of these defects are not well understood. Identifying the mechanism and targets is expected to provide leads for future development of novel therapeutics that could repair spina bifida and related birth defects in utero.
In a study using an animal model that fails to show proper neural tube closure, resulting in spina bifida, a team led by David McLone, MD, PhD, Tadanori Tomita, MD and Shekhar Mayanil, PhD showed that FA rescued the proliferation potential of neural crest stem cells from the animals via epigenetic mechanisms. Epigenetics is the study of inherited changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence. The study was published in the November 19, 2010 issue of the Journal of Biological Chemistry.
The researchers followed up with a publication in the February 2011 issue of Molecular Biology of the Cell. Pax3, a transcription factor and multifunctional regulatory protein, is expressed early in embryogenesis. In the nervous system, Pax3 is involved in neural tube closure, neural crest development, and peripheral neuron differentiation. The group examined a mechanism for Pax3 regulation of Hes1 and Neurog2 activity, and thereby stem cell maintenance and neurogenesis. They found that Pax3 acetylation, one of the key modifications that control gene transcription during embryonic development, results in decreased Hes1 and increased Neurog2 activity, thereby promoting sensory neuron differentiation (see figure below).
Senior author on these publications is Shekhar Mayanil (pictured on left), Assistant professor of Neurological Surgery at the Feinberg School, director of the Neural Tube Research Program and a member of the Developmental Biology Program of the research center. First author is Shunsuke Ichi, PhD, who is a member of the Mayanil laboratory and of the Department of Neurosurgery, University of Tokyo.