Wnt Signaling Controls The Fate Of Stem Cells In Adult Brains

After these stem cells divide, they have to choose between several options -- remaining a stem cell, turning into a nerve cell, also called a neuron, or becoming part of the brain's support network of cells called astrocytes or oligodendrocytes. According to a study published in this week's Nature, the decision to become a neuron is controlled by Wnt3 signaling molecules, which are secreted by neighboring astrocytes.

Like an unmolded block of clay, adult stem cells in the brain harbor the potential to turn into mature functioning brain cells but require additional nudging by their local microenvironment to turn into fully specialized or differentiated cells. The "nudging" comes in the form of chemical signals, but the identity of these cues is largely unknown.

"In an earlier study with Hong Jun Song, a co-author on this paper and now an assistant professor at Johns Hopkins University, we co-cultured neuronal stem cells with neurons, which gave rise to oligodendrocytes, but the same stem cells co-cultured with astrocytes isolated from the hippocampus gave rise to neurons," says Fred H. Gage, Professor in the Laboratory of Genetics at the Salk Institute and the lead author of the study.

After a lengthy and trying search, the co-first authors D. Chichung Lie, now at the GSF-National Research Center in Munich, Germany, and Sophia A. Colamarino, who since became the Scientific Director of Cure Autism Now, finally pinpointed Wnt3 as the persuasive signal molecule secreted by the astrocytes.

Wnt proteins form a family of highly conserved signaling molecules that play a crucial role in controlling cell expansion and lineage decisions in many types of stem cells.

"We blocked Wnt3 in the brain of mice with the help of molecular tools used for gene therapy, and neurogenesis decreased dramatically. When we added additional Wnt3, the number of neurons increased," explains Gage. "This increase proved to us that the Wnt signal is really important in vivo and not just a tissue culture artifact."

Many investigators have begun to explore the potential use of neuronal stem cells for the repair of circuits damaged by traumatic injury or degenerative disease, such as Parkinson's, stroke, epilepsy and Alzheimer's disease and well as depression. Identifying the molecular instructions that push neuronal stem cells down a certain path of specialization is a first step towards generating exactly the cell types needed to replace lost brain cells.

Throughout life, new brain cells or neurons are born in two small areas of mammalian brains: the olfactory bulb, which processes odors, and the central part of the hippocampus, which is involved in the formation of memories and learning. This process is called neurogenesis, which literally means "birth of neurons".

Most of these newborn cells die shortly after they are born, but some of them become functionally integrated into the surrounding brain tissue. The function of adult neurogenesis is still unclear, although a few studies have linked it to learning and memory, as well as the beneficial action of certain anti-depressants.

"All mammals retained throughout development and evolution neurogenesis in the exact same areas, but no one knows why the brain would allow new neurons to be born throughout life on in these restricted areas," says Gage. "Finally, with this knowledge of how neurogenesis occurs, we have a tool to block neurogenesis in vivo and find out what its function is," he adds.

Co-authors on this study include Salk researchers Hong-Jun Song, now at the Institute for Cell Engineering at the John Hopkins University School of Medicine, Laurent Désiré, Helena Mira, Antonella Consiglio, Edward S. Lein, Sebastian Jessberger, Heather Lansford, and Alejandro R. Dearie.

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.