NEW YORK (July 25, 2005) -- A molecule first identified by Weill Medical College of Cornell University scientists as useful in intra-cellular transport mechanisms appears to have another trick up its sleeve.

The same research team now finds that Tctex-1 may help direct the growth and development of brain cells, too.

Specifically, Tctex-1 appears to help developing neurons select which neurites - budding cellular outgrowths - will become the cell's axon and which will not. Every mature neuron has just one axon, a long skinny outgrowth that carries impulses away from the nerve cell to sites of action or sensation elsewhere in the body.

"Until now, just how the neuron picks and develops one neurite to become that single axon has been a mystery," explained lead researcher Dr. Ching-Hwa Sung, an Associate Professor of Cell Biology in Ophthalmology and Cell and Developmental Biology at Weill Cornell Medical College in New York City.

"But for the first time, we found that this molecule, Tctex-1, is uniquely expressed in young neurons in the adult brain, and especially at axonal terminals," she said.

Reporting in the July 5 issue of Developmental Cell, the Weill Cornell team, along with researchers at the Instituto Investigaci—n MŽdica Mercedes y Mart'n Ferreyra (INIMEC) in Cordoba, Argentina, found that manipulating developing neurons to overexpress Tctex-1 led to explosive axonal growth. On the other hand, Tctex-1 underexpression either stopped or slowed axonal development.

All of this is a far cry from what scientists previously knew about Tctex-1, a "light-chain" molecule that's part of a larger chemical group called the dynein complex.

"In previous work, published six years ago, we discovered that Tctex-1 is key to what we call the 'microtubular motor complex' within cells," Dr. Sung said.

In essence, they found that Tctex-1 helps direct vesicle "cargo" transfer within the nerve cells. For example, on the axon's microtubules the molecule appears to latch onto specific chemical packets, directing their transfer up and down the axon.

"It connects specific cargoes to the motor, acting as an adapter or 'hook' between these two things," Dr. Sung said.

However, as part of her ongoing research, Dr. Sung also noticed especially high concentrations of Tctex-1 within the axon terminals of young neurons that develop into mature brain cells.

"No other motor subunits shared the same expression pattern," she explained. "These findings made us think that this molecule functions outside of the motor complex and perhaps in axonal outgrowth."

This new research -- involving embryonic hippocampal progenitor cells cultured in the lab -- seems to confirm those theories.

Using a technique called RNA interference, Dr. Sung's team first suppressed normal Tctex-1 expression in these cells. "We found that if we downregulated the molecule, the neuron wouldn't even generate a neurite [bud]. So it blocked the 'sprouting' that eventually leads to the formation of axons or smaller nerve cell 'fingers' called dendrites," she said.

Then Dr. Sung's team took the opposite tack, triggering the overexpression of Tctex-1.

The results were dramatic.

"If we added it early enough, the cells developed multiple, fast-growing neurites that all had axonal characteristics. Tctex-1 seemed sufficient all by itself to do this," she said. "This occurred even when we added it during the mid-stage of development, Day 3. It was pretty exciting -- the speed of cell outgrowth extension that we saw was amazing."

So, just how does a molecule previously associated with motor-transport spur axonal development? According to Dr. Sung, Tctex-1 may serve as a kind of chemical "bridge" between two structurally dissimilar areas of the developing axon.

She explained that the main body of the axon's shaft is comprised of structures called microtubules -- the same structures that are so important to axonal motor transport. In contrast, the more distant part of the axon is characterized by another structure, microfilaments.

"Neurite outgrowth has been hypothesized to rely on some kind of 'cross-talk' between microtubules and microfilaments," Dr. Sung explained. "We now believe that Tctex-1 is involved in traffic in the microtubular area but is also released into the microfilament area. It's a kind of bridge between the two."

All of this basic science can seem very far away from practical applications, of course. But Dr. Sung said it may someday have real, clinical applications in terms of spurring neuronal growth or repair.

"We know that this molecule is very small," she said. "Clinical applications are still a long way off, but in the future, we might be able to develop some therapeutic treatment by applying Tctex-1 directly to injured neurons. This is just the beginning."

The study was funded by Research to Prevent Blindness, the Irma T. Hirschl Trust, the Ruth and Milton Steinbach Fund, the National Institutes of Health, the John Simon Guggenheim Foundation Fellowship, and the Howard Hughes Medical Institute.

Co-authors include lead researcher Dr. Jen-Zen Chuang and Dr. Ting-Yu Yeh, of Weill Cornell Medical College; and Dr. Alfredo Caceres, Ms. Flavia Bollati, Dr. Cecilia Conde, and Dr. Federico Canavosio, all of the Instituto Investigaci—n MŽdica Mercedes y Mart'n Ferreyra, in Cordoba, Argentina.