When it comes to studying how the human brain is formed, there is no better window than the glass-clear embryos of zebrafish.
Retrieved from the waters of small fish tanks with an ordinary tea strainer and studied, even video-taped, under high-powered microscopes, the embryos offer UW-Madison researchers Mary Halloran and Yevgenya Grinblat an extraordinary view of genes performing highly specialized functions that result in the construction of a healthy brain.
This in vivo peek is far preferable to studying molecules in a Petri dish. And zebrafish brains, it turns out, are enough like human brains to make these connections.
Grinblat
"They don't have a cerebral cortex, of course," says Grinblat, an associate professor in the Department of Zoology. "But many of the genes they use to create foundational brain structures are the same ones we use."
Using fluorescent proteins to light up brain regions, Grinblat and Halloran observe neural development in living fish embryos encased in transparent shells (the embryos are also transparent). Each scientist is studying different molecules, but the central question is the same: How does a functioning brain develop?
Figuring out the complex system of molecular signposts guiding neural connections is the first step in learning to recognize the flaws and breakdowns that result in developmental diseases such as autism, and neurodegenerative diseases like Alzheimer's and Huntington's.
For more than 10 years, Grinblat and Halloran have shared a zebrafish facility, developing techniques and acquiring state-of-the-art instruments to enhance their research. Together, they have created a nationally-renowned space for brain research using zebrafish. Joining them this fall is new assistant professor Marc Wolman (B.S. '02, Ph.D. '07), who says he feels like "a kid in a candy store" at the prospect of pursuing neuroscience research at UW-Madison.
Grinblat investigates the Zic gene family, common to all vertebrates. In humans, defects in Zic genes are associated with spina bifida and holoprosencephaly (a failure of the forebrain to form two hemispheres). Grinblat and her team are attempting to understand how genetic information is translated into correctly-shaped (and correctly-sized) brains. Her team's work may eventually help medical professionals administer drugs in utero that could offset potentially devastating neurological problems in humans.
Halloran
Halloran studies the development of axons, the long extensions of neurons that must grow along precise pathways to make critical connections of the nervous system. Halloran describes axon growth as tree-like.
"Axons form these very complex arbors," the professor explains. "We want to know how they grow and find their way. What controls their formation and their branches?"
Many complex developmental disorders — from schizophrenia to autism to Down’s syndrome — probably involve defects in axons' ability to grow and make connections properly.
For Halloran, an exciting discovery has involved molecules involved in "trafficking," a complex process whereby proteins are hooked to motor molecules that take them from the cell to the end of the axon. Defects in transport molecules are found in virtually every neurodegenerative disease.
"Trafficking is really important in development, but also in long-term maintenance," she says. "In later years, those neurons will degenerate and die if you have problems in the molecules that control trafficking."
The undergraduate lab course taught by Halloran and Grinblat receives rave reviews. Both professors attribute this to the joy of independent research that students discover by identifying questions, designing their own experiments, and presenting the results of a new discovery.
"There is a sense of fulfillment that comes from finding something that no one else has thought about," says Grinblat. "Learning becomes almost effortless, if we want to know."