In the United States, more than 3.5 million babies are born each year. Thanks to the fact that the US is a developed nation with advanced prenatal care professionals and resources, the majority of these babies grow up healthy.
However, many are born with birth defects because of genetic or environmental factors. And still more around the world experience these birth defects in countries with fewer medical or nutritional resources.
Sadly, some babies who are born with severe birth defects are unable to survive. Others deal with lifelong conditions which hamper their physical or mental abilities. Increased understanding of the mechanisms that cause birth defects can lead to better methods in preventing and treating birth defects around the world.
ADA Forsyth Senior Investigator Chengji Zhou, Ph.D. has dedicated much of his 20-year career to researching tissue closure birth defects, including neural tube defects and orofacial clefts. A neural tube defect occurs when the precursor structure that eventually grows to make up the spinal column and brain does not close properly during early embryonic development.
Through R01 research grants awarded by the National Institutes of Health (NIH), Dr. Zhou and his team address the mechanisms by which neural tube defects occur.
“This work is focused on future generations – so healthy babies can be born, and neural tube defects may be prevented through maternal interventions early in pregnancies,” Dr. Zhou said.
Neural tube closure takes place in the early embryonic stage, after the formation of three primary germ layers: ectoderm, mesoderm, and endoderm. The neural plate arises from the ectoderm and closes to form the neural tube, which eventually develops into the brain and spinal cord. The closure process completes quickly in the fourth week of pregnancy – often before a woman knows she is pregnant.
Neural tube closure is rather vulnerable to genetic mutations or environmental factors that can cause neural tube defects, one of the most common and severe structural birth defects.
Spina bifida, the common form of neural tube defects in which the spinal neural tube does not completely close, occurs in 1 in every 2,875 births per year in the US. In craniorachischisis, the rarest but most severe neural tube defect, the brain and spinal cord remain open at birth.
In 1980, an important study on vitamin supplements for pregnant women established that folate can effectively decrease neural tube defects. The US Public Health Service’s 1992 mandate to fortify foods with folic acid led to decreases in spina bifida by 31% and decreases in anencephaly by 16%.
However, neural tube defects still occur after implementation of folic acid food fortification policy in developed countries. These defects are considered folate unpreventable or folate resistant.
Dr. Zhou and his team use mutant mouse models to study the mechanism and intervention of the folate-untreatable neural tube defects, by focusing on spina bifida.
In his lab at UC Davis, Dr. Zhou’s team discovered novel mechanisms and cellular dynamics in mouse models that direct neural tube closure. They identified the rosette formation in which non-neural surface ectodermal cells converge to direct spinal neural tube closure. Gene mutations that disrupt this rosette formation can cause spina bifida.
“Sometimes, science and art come together in a very beautiful way,” Dr. Zhou said, as he explained how the closure of the neural tube resembles a flower blooming.
As Dr. Zhou discovered, a very small number of cells – a few hundred cells – play a part in the closure of the neural tube as non-neural surface ectodermal cells close the neural tube through their rosette formation and convergent cytoskeletal protrusions.
Single-cell genomics – the study of the genomes of individual cells – can help Dr. Zhou’s team dig deeper into the characteristics of the small group of cells at work in neural tube closure.
“Studying the activities of gene expression and signaling pathways and gaining a deeper understanding of neural tube closure can build a strong foundation for translational studies of neural tube defects,” Dr. Zhou said.
