Mid-Atlantic Consortium Newsletter Summer 2013

Ask the Expert: Irene Zohn, PhD

Dr. Zohn is Principal Investigator, Children’s Research Institute Center for Neuroscience Research at Children’s National Medical Center

Irene Zohn, Ph.D.Although birth defects of the brain and spinal cord known as neural tube defects represent some of the most common birth defects, their causes remain poorly understood. Neural tube defects result when tissues that normally surround the brain and spinal cord fail to do that completely. This incomplete closure results in brain and skull defects, and in the spinal cord results in spina bifida, a condition marked by malformations of the spine and various degrees of paralysis, incontinence, and learning difficulties. Many instances of neural tube defects can be prevented by providing pregnant women with multivitamins containing folic acid (Vitamin B9).

Developmental biologist Irene Zohn has been studying the molecular pathways that regulate neural tube closure, as well as the impact of iron deficiency on neural tube defects in mice. Her work has won awards from the Spina Bifida Association and the March of Dimes. She spoke to Collaborations about some of her recent research.


Q: Why don’t we know more about neural tube defects?

A: Neural tube defects are hard to study in humans because there are both genetic and environmental causes. However, recently, a few of the genes found to be responsible in mice have also been found to be mutated in human spina bifida patients. We’re trying to get an idea of the important genes and pathways in mice to provide us with promising targets for human studies.


Q: What do you hope, ultimately, to learn?

A: My goal is to find out which specific genes and pathways are involved in neural tube development, how their disruption leads to neural tube defects, and what strategies can prevent them. I study basic biology and try to ask how the mechanisms identified in model systems can be used to develop treatments to prevent neural tube defects in humans.


Q: What about folic acid in multivitamins? Is it helping reduce rates of neural tube defects?

A: Actually, people don’t take (vitamins) very consistently. Neural tube defects develop during the fourth week of pregnancy before many women realize that they are pregnant. At that point it is too late to take folic acid to prevent neural tube defects. Also, since many pregnancies are unplanned, recommending that women supplement has not been very effective. Because of this, the United States and many other countries have decided to supplement the food supply with folic acid. In the U.S., foods like flour and breakfast cereals are fortified with folic acid. Since the implementation of this policy, rates of neural tube defects have been going down. In the U.S. the incidence is about 1 in 1,000 births or less, but in some parts of the world, like a particular region of China, the rate has been as high as 1 in 100.


Q: What’s the latest in your research?

A: Several mouse models of neural tube defects have been developed. In one of our mouse lines, we identified a mutation in the gene encoding ferroportin 1 (Fpn1), a protein involved in iron metabolism. Interestingly, Fpn1 is not expressed in the neural tissue itself, but in the cells responsible for delivering nutrients to the developing embryo. We did some mouse genetic and embryo culture studies and discovered that neural tube defects in this mouse line were due to severe iron deficiency during neural tube closure. Furthermore, we could prevent neural tube defects in this mouse line by supplementing the mothers-to-be with a high iron diet. We believe our data demonstrates for the first time rigorously that iron is essential for closure of the neural tube. We’re now planning to study the interaction of iron and folic acid by systematically studying the effects of folic acid, iron, and the combination on risk of neural tube defects in these mice. We also have collaborations with other researchers to look at human populations to see if iron plays a role in neural tube defects.

Another one of our genetically engineered mouse lines is deficient in another gene,  Hectd1, which I have found to be necessary for closure of the neural tube. Our most recent study found that Hectd1 modifies a protein called Hsp90. Without Hectd1, too much Hsp90 is secreted, which in turn disrupts the process by which organs develop normally. All of this leads to incomplete closure of the neural tube and an “open brain” phenotype. We are trying to understand how disruption of this pathway causes abnormal development and what can be done to prevent that from happening.


For more information about Zohn’s research, see http://www.childrensnational.org/research/faculty/bios/cnr/zohn_i.aspx.

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