Using see-through fish as a window on brain formation
March 9, 2015
By Rachel Tompa
When Dr. Cecilia Moens reflects on her decades of research uncovering the genes and proteins that craft and shape the brain, she likes to give credit where credit is due — to the tiny freshwater fish whose unique characteristics make her work possible.
Moens studies zebrafish embryos, which develop outside their mother and are nearly completely transparent, having evolved to hide from predators by looking as much like empty water as a defenseless baby fish can. For Moens that evolutionary adaptation comes with the added bonus that she can watch these junior fish form their brains in real time, peering through their see-through heads.
“I’m a very visual person, as lots of people are,” Moens said. “For me to be able to see the process that I’m interested in studying, looking down a microscope at a living embryo, that makes all the difference.”
Although Moens’ esteem for zebrafish is clear, she’s in it for what the creatures can tell us about our own brains. Many steps in the early stages of zebrafish brain development are, gene by gene, cell by cell, replicated in humans.
“They’re undergoing all those developmental steps that your brain or my brain underwent in the first few weeks of our development,” she said.
By unpicking those steps, Moens and her laboratory team in Fred Hutchinson Cancer Research Center’s Basic Sciences Division are discovering not only what makes a human brain tick, but what may go awry in developmental disorders that affect the brain – disorders like autism, spina bifida, or the rarer Joubert and Nance-Horan syndromes.
Although human geneticists identify the mutations that underlie these diseases, developmental research is essential to truly understand the genes, neurons and pathways of molecules that shape each part of the brain. So when biologists find a gene that plays a role in a human disease, there is already a wealth of knowledge about that gene generated by scientists like Moens.
“They’re never starting from ground zero anymore,” Moens said. “What we do as developmental biologists is highly relevant to human developmental disorders.”
What Moens and other developmental biologists study is also relevant to understanding how cancer works, one of the reasons Moens set up her laboratory at Fred Hutch. Many of the things cells do during development — divide rapidly, travel through the body, burrow into new tissue — are replicated when cancer forms, albeit in an incoherent, unorganized fashion.
“Cancer cells are running through a kind of Rolodex of what’s available to [them] for what [they] need to do,” Moens said. “And what cancer cells have available to them are developmental signaling pathways.”
So understanding those pathways means, ultimately, learning more about cancer.
Moens studies how events very early in embryonic development trigger cascades that lend each neuron its own unique identity, behavior and how it connects to other neurons.
In a recent study looking at the neurons and special synapses that form in the first few days of a zebrafish’s life, a neural setup that primarily allows the baby fish to swim away from predators, Moens and her team found that a gene implicated in human autism spectrum disorders also plays a role in the formation of synapses of that neural circuit. Although humans don’t have the same kind of reflexive escape behavior, Moens’ work implies that the special synapses involved — known as electrical synapses — could play a role in autism, a connection that had never previously been drawn.
In another research avenue, Moens and her team have identified proteins involved in neuron migration early in brain development. Most neurons arise in special zones in the brain but migrate to their final home elsewhere in the brain where they make functional connections; the researchers used real-time visualization of 2-day-old zebrafish to watch the neurons "walk" along their neighboring cells to their new dwelling spot and to discover the molecules responsible for that migration.
That research would not have been possible in any system other than the fish, Moens said. When the scientists tried to take the migrating neurons out of the fish and study them in a petri dish, they didn’t do anything – their fate is too closely tied to the signals of their native milieu.
“What we can do now, today, in zebrafish is really amazing,” she said.
Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Research Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel Tompa.