UCSD and Japanese researchers identify new gene involved in development and function of central nervous system

December 20, 2000

A new gene directly involved in the migration of neurons to the developing brain, and then in the ongoing function of the mature central nervous system, has been identified and described by researchers from the UCSD School of Medicine and the Shirakawa Institute of Animal Genetics in Japan.

One of the mysteries of human development is how the vast number of cells that are produced following fertilization of an egg are deployed to create a human being. In the December 2000 issue of the journal Neuron, the research team describes a protein called "NUDEL". NUDEL plays a critical role as part of a transport complex that includes LIS1, a protein identified in human patients with a severe neuronal migration defect. Together, these proteins regulate the function of motor-molecules called dyneins that transport cellular cargo such as organelles within the cell. This complex helps newly formed brain cells migrate to specific regions of the embryonic brain, ensuring proper development of the cerebral cortex, the center of intellectual and cognitive function.

"The discovery of NUDEL helps us to fill in the details about how neurons in the developing brain become wired. It provides some new information about the way embryonic neuronal cells divide and travel to end up in the right place at the right time in order to make the proper connection in the adult brain," said Anthony Wynshaw-Boris, M.D., Ph.D., UCSD assistant professor of pediatrics and medicine and co-author of the Neuron paper.

"As we increase our knowledge of neuron migration and the pathways by which the proper connections are made, we might discover new approaches to treating neurodegenerative diseases linked to breakdowns in this transport system," added Shinji Hirotsune, M.D., Ph.D., of the Shirakawa Institute of Animal Genetics. "We might also be able to develop innovative ways to repair lesions using these pathways to deliver therapies directly to the diseased part of the brain."

Human defects in neural migration leading to structural defects in the brain have been linked to many disorders, such as epilepsy and schizophrenia. One devastating example is lissencephaly, manifested by a smooth brain surface and a disorganized cortex. Children with lissencephaly suffer profound mental retardation, increasingly severe epilepsy, and early death. Nearly 10 years ago scientists identified mutations in a gene called LIS1 as one of the primary causes of lissencephaly. Subsequent research by several laboratories has shown that this gene is essential for the regulation of neuronal migration. When the gene is mutated in humans and mice, the number of neurons in the brain appears to be reduced, with a resulting profound defect in structure and organization of the brain. However, the molecular and cellular functions underlying the role of LIS1 in this process have not been well-defined.

In their Neuron paper, researchers from the laboratories of Wynshaw-Boris and Hirotsune establish that the LIS1/NUDEL complex binds with dynein motor-molecules. NUDEL is activated by the addition of a phosphate group via an enzyme complex called CdK5/p35, which has been shown in previous studies to be essential for neural migration. NUDEL is closely linked to LIS1 on human chromosome 17 and mouse chromosome 11.

In studies of mice, the researchers show that once the brain is formed, this transport complex moves into the neuronal axons, the long tendrils that sprout from neurons to connect cells in the central nervous system or the body's extremities. There, the NUDEL/LIS1/dynein complex may be instrumental in transporting cellular material up and down the axon.

According to the researchers, the LIS1/NUDEL complex also appears to play an important role in cell division and cell proliferation as well as in cell survival. For example, this complex appears to play a role helping to allocate the chromosome complement properly during cell division or mitosis as the mother cell gives rise to two new cells. These are intriguing findings that require further study, the scientists said.
The research was supported by grants from the National Institutes of Health, the Howard Hughes Medical Institute and UCSD School of Medicine funds.

In addition to Wynshaw-Boris and Hirotsune, the authors were Shinji Sasaki, Aki Shionoya and Michiyo Ishida, Shirakawa Institute of Animal Genetics; and Michael Gambello and Jessica Yingling, UCSD School of Medicine.

University of California - San Diego

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