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A Big Surprise: Young Nerve Cells Can Rewind Their Developmental Clocks
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| Order in the Cortex. The bright red spots in these images are Cajal-Retzius (CR) cells. Normally, these cells only appear in layer 1 of the cortex. The upper image, showing a thin line of CR cells on the top, reveals the normal development of the six cortical layers. The lower image shows what happens when the gene Foxg1 is eliminated in embryonic mice: CR cells appear in all the layers of the cortex. |
In a new study, NYU School of Medicine researchers report that a gene called Foxg1 at least in part controls the orderly production of cortical layers. This finding stems from the observation that when the gene is eliminated in mice, the developmental clock in young cortical cells can be rewound. Their study is published in the January 2, 2004 issue of Science magazine.
"What we found was a complete surprise," says Gordon Fishell, Ph.D., Associate Professor of Cell Biology. "No one had believed that it was possible to push back the birth date of a cortical neuron. There is this central tenet governing the process of brain development, which says that late progenitor cells [forerunners of mature cell types] cannot give rise to cell types produced earlier in development," he explains.
The researchers asked which cortical cell types embryonic mice lacking Foxg1 can generate. Carina Hanashima, Ph.D., a postdoctoral fellow in Dr. Fishell's laboratory, conducted a series of experiments that made the analysis possible.
The progenitor cells for the cortex are born in a zone deep in the brain, and migrate to their assigned layer, depending on the time they are born. So a cortical cell's identity is based on the date of its birth. The first cortical cells to be born populate layer 1, the most superficial layer, which is made up of special Cajal-Retzius (CR) cells. The next cells born migrate to the innermost layer, layer 6. Each layer has a specific type of neuron associated with it.
The researchers looked at the cortical layers in embryonic mice at a time in their development when layers 1, 6, and 5, would normally have already been formed. In mice lacking the Foxg1 gene, the researchers found that only layer 1, which is made up of CR cells, was present, and these cells were abundant. The absence of other cell types implicated the gene in producing later- born cortical cell types.
In subsequent experiments, the researchers asked how the overproduction of CR cells occurs. They used a clever biochemical manipulation that served as a kind of genetic stop watch, allowing them to temporarily turn off the Foxg1 gene in late progenitor cells, after the normal birth date of CR cells had passed. In this way, they observed that cortical cells destined to become layer 5 became CR cells instead. When the gene is inactivated or turned off, the program seems to revert to its earliest stage.
The researchers do not know how late they can play their genetic tricks. If they turn off the Foxg1 gene at a later time in development, such as when cortical layers 2 or 3 are forming, will progenitor neuronal cells still become CR cells? Are there other genes that control the developmental clock? If such genes exist, it may be possible to turn these genes off in adult neural stem cells, and thereby generate a far broader array of tissue than otherwise possible. "I would say that the chances of this happening are very remote," says Dr. Fishell, "but then again, I never thought that the clock could have been turned back in neuronal progenitor cells."
The authors of the study are Gordon Fishell and Carina Hanashima of
NYU School of Medicine; Eseng Lai of Merck; Suzanne Li of Memorial Sloan-Kettering
Cancer Center; and Lijian Shen of Weill Medical College of Cornell University.