The fine art of brain development  pg. 4

Death signal

Motor neuron expressing different colored fluorescent proteins in a C. elegans larva.
Image courtesy of David Miller, Ph.D., Vanderbilt Department of Cell & Developmental Biology
One of the more curious aspects of nervous system sculpting is the natural overbuilding that occurs. More neurons are produced than we will ever need or use—and thus are eventually “chipped away.” About half of all neurons born will die through a pre-programmed “suicide” mechanism called apoptosis, says Bruce Carter, Ph.D., professor of Biochemistry at Vanderbilt.

“In some places, you lose all the neurons,” he explains. “In other places you lose 10 percent. It varies, but about half of the neurons generated die—it’s a normal pruning process.”

The delicate balance between life and death of brain cells is centered on a family of molecules called neurotrophins. This family includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophins 3 and 4 (NT3 and NT4), and has been an intense area of focus for Carter and colleagues.

The neurotrophins can bind to two different classes of receptors embedded within the neuronal membrane: the Trk family of receptors, which usually promotes survival, and the p75 receptor, which can promote either survival or cell death.

The dual role of p75 had baffled researchers. “It was already known for 50 years that NGF promotes survival,” Carter says. “So the idea that somehow the receptor for NGF could cause cell death didn’t really make any sense.

“However, what we’ve learned is that neurons that get the ‘right’ neurotrophin first will survive through a combined Trk-p75 signal, and they start producing a different neurotrophin, which acts through p75 alone to cause death of their neighbors. Thus, there is a beautifully regulated competition set up so that the proper connections are efficiently established.”

How these factors produced such opposing signals was still a mystery. Several years ago, while investigating how these conflicting signals are generated by p75, Carter and colleagues discovered a protein, called NRIF (neurotrophin receptor interacting factor), that binds to part of the receptor and appears to be required for p75-induced cell death. NRIF resembled well-known transcription factors that alter gene expression within the nucleus. The Vanderbilt researchers and others had also determined that NRIF entry into the nucleus induced apoptotic cell death.

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