How Stem Cells Build a Complex Brain

Guest post by science writer Carl Sherman

Within the brain’s complexity is the diversity of its 10 billion neurons: large, small, thin, fat, connected by long fibrils or short bushy ones. Some produce the neurotransmitter serotonin; others dopamine or norepinephrine. How this abundance of forms arises is a mystery we are just starting to penetrate.

It’s of more than mere theoretical interest, says Minoree Kohwi, Ph.D., assistant professor of neuroscience at Columbia University. “Knowing how the brain is built, piece by piece, from the ground up, may give critical clues as to what goes wrong to cause diseases, and ultimately help us prevent or cure them.” It may even, someday, allow us to make neurons to replace those lost to injury or aging.

At last Wednesday’s talk, hosted by Columbia’s Mind Brain Behavior Institute and sponsored by the Dana Foundation, attendees glimpsed these possibilities as Kohwi described her research.

She took us back to the beginning—the 30th day of gestation, when neural stem cells (NSCs) appear. These few ancestors of all cells in the brain must change repeatedly in the course of development to produce such diverse progeny.

The secret, she said, is in the genes.

All cells in the body have the same genes. “But each cell only activates some of them. What makes a type of neuron unique is the subset of genes that instruct it to take on its distinctive properties,” Kohwi said. It’s apparently by expressing and then silencing genes that NSCs produce different neurons, she explained.

To study this process, Kohwi turned to fruit flies, tiny insects with speck-sized brains that have surprisingly much in common with us: roughly the same number of genes—about 20,000—including many that correspond to ours.

“Over 75 percent of genes related to human diseases seem to have a match in fruit flies,” she said. For example, the gene that mutates in fragile X syndrome, the most common genetic cause of autism, also appears on the fruit fly genome, giving scientists an invaluable tool to probe the disorder and screen for compounds that might reverse it.

The fruit fly develops rapidly: within 24 hours, its central nervous system arises in a “ventral nerve cord” (analogous to our spinal cord) that wraps around the embryo. Its neural stem cells are relatively few, and “each can be accounted for: we know exactly where it is during development, what type of neuron it is making, and when it is making it,” Kohwi said.

The fruit fly embryo [Turner, F.R. and Mahowald, A.P.  (1979)]. Scanning electron microscopy of Drosophila melanogaster embryogenesis. III. Formation of the head and caudal segments. Dev. Biol. 68: 96-109], with  a superimposed fluorescent image of the ventral nerve cord, in which the magenta circles are neural stem cells and the smaller green cells the layers of neurons born from them. Photo courtesy of Minoree Kohwi.

The fruit fly embryo [Turner, F.R. and Mahowald, A.P. (1979)]. Scanning electron microscopy of Drosophila melanogaster embryogenesis. III. Formation of the head and caudal segments. Dev. Biol. 68: 96-109], with a superimposed fluorescent image of the ventral nerve cord, in which the magenta circles are neural stem cells and the smaller green cells the layers of neurons born from them. Photo courtesy of Minoree Kohwi.

Using high resolution optics, Kohwi and her colleagues can follow a NSC’s repeated divisions as it buds off neurons. “Over time, the NSC changes expression of its genes, and these genes confer specific properties to neurons born during that division.”

Kohwi offered an inside look at one such cell, neuroblast 7-1, as it went through these changes. When it started dividing, it expressed a gene the researchers termed “hunchback.” When hunchback went silent, the “pdm” gene took over; then, it was time for “castor.” Successive generations formed layers in the ventral nerve cord.

When a neuron is born governs what type it becomes—those born while the neural stem cell is expressing “hunchback” will take on properties completely different from after it switches to ‘castor,'” Kohwi said.

This same process steers mammalian development and organizes the functional circuitry of many brain regions. Neurons in the human cortex, for example, occupy six layers corresponding to birth order, each with its own properties and connections.

Recent work in Kohwi’s laboratory illuminates the underlying molecular mechanics: why NSCs become unable to make earlier neuron types when they start generating new ones.

Apparently, location matters. Using fluorescent chemical tags, “I can track what happens to a single gene in a single neural stem cell in the course of development,” she said. She saw that after Neuroblast 7-1 stopped producing neurons with “hunchback,” that gene migrated from the interior to the edge of the nucleus, near its membrane, which acts as kind of storage facility. The NSC genome reorganizes itself, in other words, changing the accessibility of certain genes.

“This is the start of something really new and really exciting,” Kohwi said. “We don’t yet know if this type of mechanism occur in mammalian NSCs, but it’s something we hope to uncover in upcoming years.

“The Human Genome Project has given us the linear sequence of our DNA. What we want now is to go the next step and understand how the linear sequence is folded in three dimensions within the cell’s nucleus, and how this 3-D organization controls which genes are turned on or off.

“I think that will be the key to harnessing the true power of NSCs,” she said.

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