Researcher Pinpoints Gene Culpable for Neural Defects

A UC Berkeley graduate has discovered a way to monitor for fetal spinal cord defects. Saori Haigo, a 2003 graduate currently in her first year at Harvard Medical School, concluded that activation of a single gene initiates these neural tube problems.

The gene, referred to as "shroom," (short for mushroom) was found to be required for neural tube closure by Jeff Hildebrand at the University of Pittsburgh. Hildebrand demonstrated that shroom caused cells in the embryo to bend, forcing the tissue to curl into a closed neural tube that together formed the spinal cord and brain.

In establishing collaboration with Hildebrand to study the cellular function of shroom, Haigo was supervised by UC Berkeley molecular and cellular biology professors Richard Harland and John Wallingford.

"Our lab at Berkeley took an in vivo approach to study shroom function in the developing frog embryo," Haigo said. "We thought shroom was a particularly good candidate to study because it interacted with other components that make up the cell's architecture to affect cell shape."

Since frog development occurs externally, Haigo ran tests to demonstrate that shroom induces apical constrictions. Apical constrictions involve the cell changing shape from a columnar shape to a bottle or wedge shape.

"You can think of it like a cylindrical Coke can getting pinched at the top to end up looking like a Coke bottle," Haigo said. "Apical constrictions are important during the development of many animals because it creates bends in the body so you can get a variety of morphologies."

To demonstrate that shroom induces apical constrictions needed for proper neural tube closure, three key issues were addressed. Shroom needed a distinct expression pattern during neural tube closure to prove that the gene was expressed at the right time and place for the closure.

By introducing shroom to a naïve population of cells that don't normally express shroom, Haigo observed that shroom induces apical constructions in naïve epithelial cells. To confirm that shroom is necessary for neural tube closure, shroom function was blocked.

"When we introduced inhibitory reagents that blocked shroom activity, we found that we could get the same neural tube defect as seen in the shroom mutant mouse," Haigo said. "However, we were able to go farther by demonstrating that shroom is necessary for hinge point formation during neural tube closure."

According to Haigo, as much as 30 percent of neural tube defects have a genetic basis that is poorly understood. Defects such as spina bifida, an open spinal cord, and anencephaly, or lack of a complete brain are common in the United States.

The understanding of shroom as vital to the neural tube closure process advances the medical field.

"We hope to prevent such debilitating birth defects from happening by understanding this process and developing therapeutic agents that may circumvent such defects from forming," Haigo said.

The McNairs Scholars Program and the Haas Scholars Program supported Haigo's undergraduate research.

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