Glimpse into early brain development shows how nerve cells move into position

Tucked into the lower, rear portion of the brain, the cerebellum plays key roles in motor learning, motor memory and sensory perception. It's also where the majority of metastatic childhood brain tumors are located. Yet scientists still know very little about its early growth.

Now, new research has pinned down how cells in the cerebellum migrate and differentiate during the first stages of brain development, and shows that different combinations of regulatory proteins called transcription factors are responsible for driving these changes.

Transcription factors are proteins that can turn genes on or off, or even just fine-tune a gene's activity. According to the new research, published in the Journal of Neuroscience by Mary E. Hatten, Frederick P. Rose Professor and head of Rockefeller University's Laboratory of Developmental Neurobiology, and Daniver Morales, a postdoctoral fellow in the lab, precise patterns of activity of transcription factors in the brain are responsible for defining the three major types of neurons in the cerebellum. And these specific transcription factor patterns, combined with the young neurons' migration pathways, appear to generate the cerebellum's two fundamental structures: the cerebellar nuclei and the cerebellar cortex.

Using newly developed transcription-factor pattern markers, in conjunction with fluorescent microscopy, Hatten and Morales found that they could visualize the three types of neurons that make up the cerebellum: deep nuclei, located in the very center; Purkinje cells, which are some of largest neurons in the brain; and the tiny, plentiful granule cells, which make up the cerebellar granule layer. From there, the researchers could follow the generation and migration of these cells in the developing brain.

"We found that cell migration pathways have exquisite timing, and we see this amazing tango as different populations of cells zoom into place," Hatten says. One of the most notable observations that the researchers made was that their markers allowed them to image the youngest Purkinje cells ever seen, and to follow the cells as they migrated into position along neural support cells called glia. "This was something that everyone had always assumed, but had never actually been proved," she says. And Purkinje cells weren't the only ones to use glia for migration. "Neurons of the cerebellar nuclei migrate on glia too - that was a real surprise."

Hatten and Morales found another surprise in their data, one that may have implications for understanding brain cancer: By watching the different transcription-factor patterns, they found that granule cells may be developing from different subsets of cells. "The granule cell is the generator of the medulloblastoma, the cancer responsible for 40 percent of all pediatric brain tumors," Hatten says. With 15 different kinds of medullablastomas, it's quite possible that the different types of tumors may be originating from different subtypes of granule cells.

"The different gene patterns of the granule cell subtypes are going to define new experiments that physiologists can use to understand the neurology of the cerebellum," Hatten says. "And they're going to help us understand this part of the brain that's implicated in pediatric brain tumors."

Journal of Neuroscience 26(47): 12226-12236 (November 22, 2006)

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