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How the brain organizes itself: a bit of nature, a bit of nurture ". . . at a certain stage there emerges a single cell which will have as all its progeny the human brain. The mere existence of that cell should be one of the great astonishments of the earth." -- Lewis Thomas, "On Embryology," from The Medusa and the Snail: More Notes of a Biology Watcher

Susan McConnell is working to solve a piece of the puzzle that so amazed the great essayist: how the developing embryo builds the trillion-cell connections of the brain from the offspring of those primitive progenitor cells.

"The analogy is, how would you hook up the phone system around the world starting from scratch, so that your call from San Francisco reaches London and not Tokyo by mistake," McConnell said.

In an article published in the Oct. 13 issue of Science, McConnell and research assistant Christine Kaznowski answer the question of whether it is nurture (something in the brain environment) or nature (instructions inside the cells themselves) that determines where a newborn cell will migrate and make its connections in the eventual adult brain.

The answer: both. The brain's nurture of the mother cell determines the nature of the daughter cell.

McConnell and others have already shown that the six layers of the cerebral cortex are formed one at a time, and that the same progenitor cell that makes new cells for Layer 6 will later make cells destined for other layers as well. Each new cell's fate is linked to its "birth date."

"The question really is, what is the nature of the influences that determine the fate of these cells?" McConnell said. "Is it something intrinsic, or is it really the environment in which a cell grows that plays a role in directing it to a particular occupation?"

Using a new technique that allows them to label and transplant neuronal cells, McConnell and Kaznowski took newly hatched cells from the brains of ferret embryos and transplanted them into the slightly older, but still developing brains of newborn ferrets.

Even though the recipient brains were developing a new upper layer of cortex, the transplanted cells migrated and established connections in the same deep layer that was appropriate to their birth dates.

McConnell said, "This means that a newly generated neuron is already equipped with all the information it needs to get to the right layer and form the right connections."

The story has a twist, though. When progenitor cells were transplanted very early in the cell cycle, just as each was beginning to replicate DNA to produce a daughter neuron, those daughter cells changed their fates. They migrated to the layer appropriate to the older neurons in the recipient animal's brain.

"The environment plays a very important role in sculpting the fate of a particular neuron," McConnell concluded. "Only it does it during a critical window of time during the cell cycle.

"Once the environment has had a chance to communicate to the progenitor cell and say, this is the daughter cell needed at this time in development, then a switch seems to be flipped. The daughter neuron is committed to a fate typical of its birthday."

McConnell's lab continues to look for clues to how the developing brain communicates to the progenitor cells, and how daughter neurons recognize cell surface molecules or some other signal as they migrate to the appropriate layer of the cortex.

When Lewis Thomas wrote his essay a dozen years ago, he said about the building of the brain: "One cell is switched on to become the whole trillion-cell, massive apparatus for thinking and imaging. . . . No one has the ghost of an idea how this works, and nothing else in life can ever be so puzzling."

McConnell and other developmental neurobiologists have raised the ghosts of ideas about the process now, but they are still a distance from reaping Thomas' reward:

"If anyone does succeed in explaining it, within my lifetime," he wrote, "I will charter a skywriting airplane, maybe a whole fleet of them, and send them aloft to write one great exclamation point after another, around the whole sky, until all my money runs out."


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