wenty years ago, Anthony LaMantia would have laughed if someone had told him that someday he’d be studying the origins of limbs or hearts or faces. He was a neurobiologist, and neurobiologists don’t study just any old cell. They study neurons. Brain cells. But today his work is showing that a front lobe of the brain is made using the same embryonic cells and the same processes that are used in creating the limbs, the heart, and the face.

LaMantia’s research wouldn’t be on this path without the increasingly powerful tools of genetics and the serendipity of an unexpected collaboration. Both are themes repeated over and over at Carolina’s new Neurosciences Research Center, where director Bill Snider, a soft-spoken professor of neurology and of cell and molecular physiology, has recruited scientists from a wide variety of fields who all want to find out one thing — how do you make a brain?

LaMantia’s work began taking its unexpected turn as he and his lab were investigating the very early development of the forebrain — the "heavy hitter" front region that’s involved in human thought, emotions, and behavior. It’s not well understood how the forebrain is differentiated — how its pieces get in the right places.

It turns out that one answer to that question is a process called mesenchymal/epithelial (M/E) induction. LaMantia, associate professor of cell and molecular physiology, explains this tongue-twisting term. "There are two types of cells in an embryo — epithelial cells, which are arranged in sheets, and mesenchymal cells, which are loosely accumulated groups in between those sheets." M/E induction is the signaling between these two groups of cells.

By studying mouse embryos, LaMantia’s group found that M/E induction plays a role in differentiation of one part of the forebrain. This finding was doubly interesting because other researchers had already established that M/E induction is critical in the development of the limbs, craniofacial features, and the heart. It’s hard to imagine that such different parts of the body develop by the same process. LaMantia explains it by comparing the development of the brain to building a skyscraper, and the development of the hands to building a small house. For the skyscraper you need cranes and bulldozers, for the house you don’t. But some common tools — screwdrivers, hammers, and nails — are used in building both.

aMantia’s group has also found that one particular signaling molecule, retinoic acid, is important for driving early development of the forebrain. Retinoic acid, actually a form of vitamin A, is also known to play a role in development of, yes, the heart, limbs, and face. This role became painfully clear in the early 1980s when pregnant women who took the acne medicine Accutane, which is a relatively small dose of one form of retinoic acid, had babies with serious, usually fatal, defects of the heart as well as malformed limbs and faces.

There’s another link between the brain and those other areas of the body, and LaMantia became aware of it quite by accident. In 1999, the National Institute of Mental Health asked him to present some of this work at a meeting of psychiatrists. After the talk, Jeffrey Lieberman, professor of psychiatry at Carolina, approached LaMantia to talk about schizophrenia. The disorder wasn’t completely unrelated to LaMantia’s work because it is generally thought that the causes of schizophrenia lie in early brain development. Still, LaMantia was no clinician.

But the connection became clear when Lieberman (and later Lin Sikich in Lieberman’s group) began talking to LaMantia about a disorder called Veliocardiofacial syndrome (VCFS) whose sufferers not only have limb, craniofacial, and heart malformations, but also a high incidence of schizophrenia — 25 times the rate in the general population. This anecdotal information about humans supported LaMantia’s findings in mice — that development of the limbs, face, and heart may be somehow related to development of the brain.

"It encouraged us that it really was a viable hypothesis that all of these sites use the same set, the same basic cellular mechanism," LaMantia says. And Lieberman’s insight also pointed LaMantia to another avenue — the genes known to be deleted in VCFS.

LaMantia cloned these genes in mice and looked to see where the genes were expressed — where they encode a message. Out of 28 genes, 19 were expressed in either the forebrain, the limbs, the heart, or the craniofacial structures. And 17 of those 19 genes were expressed in the brain throughout life.

"That means that these genes have dual access to mess up the brain," LaMantia says. The finding means it’s plausible that mutations in these genes could contribute to schizophrenia, given that the "two-hit" model of the disorder is becoming accepted. This idea suggests that during development some genes are disrupted slightly and are still vulnerable years later, when a second trauma occurs in late adolescence — the time that schizophrenia symptoms usually make their first appearance.

"Certainly we’ve stumbled into a whole subset of genes that have clear relevance for human health and disease," LaMantia says. "I’d be the first one to tell you that we’re not going to understand schizophrenia by looking at the function of these genes in the mouse. But we’re going to provide insight into what this subset of genes does when you’re making the brain and during later life when you’re maintaining it. That insight may help other people look at the functions of those genes in clinical populations."