Lunatic Fringe Gene Plays Key Role in Renewable Brain

A long-standing misconception in biology, until recently, had been that the adult brain did not generate new neuronal cells. However, the point of fact is that the brain can produce slightly under a thousand new neurons per day on average. Yet, how this process is regulated molecularly is still a bit of a mystery to researchers.

Researchers at Baylor College of Medicine and Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital have developed a novel mouse model that for the first time selectively identifies neural stem cells, the progenitors of new adult brain cells.

In these mice, researchers have found a novel mechanism by which descendants of neural stem cells can send feedback signals to alter the division and the fate of the mother cell.  Results from this new study were published recently in eLife in an article entitled “Lunatic Fringe-Mediated Notch Signaling Regulates Adult Hippocampal Neural Stem Cell Maintenance.”

“Our initial goal for this study was to find a gene that is selectively expressed in primary neural stem cells,” explained senior study investigator Mirjana Maletic-Savatic, M.D., Ph.D., assistant professor of pediatrics and neurology at Baylor and Texas Children’s Hospital. “Based on the information obtained from publicly available expression databases, we started with roughly 750 potential candidate genes. It took an enormous amount of hard work and meticulousness to systematically narrow it down to a single gene—it was like looking for a needle in a haystack. After extensive analysis, we were convinced that the gene lunatic fringe, a member of the well-studied Notch signaling pathway, was the selective marker of neural stem cells.”

At the end of their “vision quest” to categorize the pathways involved in the regulation of stem cell fate, the researchers did identify the lunatic fringe (LFNG) gene as a selective marker for neural stem cells. While previous studies in a number of animal models had shown that members of the Notch signaling pathway participate in the regulation of stem cell fate, the LFNG discovery represents a potentially significant step forward in the field of neurogenesis—as the precise mechanism and the fine-tuning of Notch signaling in the hippocampus of the adult brain had remained elusive until now.

Since neural stem cells and their progeny physically cluster around one another, this is an ideal environment for direct cell–cell communication between neural stem cells and adjacent cells. Interestingly, the investigators found that lunatic fringe allows neural stem cells to distinguish between and respond differently to surrounding cells expressing other markers, in particular, those expressing the Delta and Jagged1 markers.

When surrounded by Delta neurons, most neural stem cells remain in a standby mode, protected from random activation and unnecessary division. Conversely, when neural stem cells interact with Jagged1 neurons, they begin to divide. Collectively, these processes allow division of every neural stem cell to be finely regulated to prevent excessive division and premature exhaustion of its potential.

“This study and the mouse model we have generated represent a huge step forward in the field of neural stem cell biology because now we not only have a benchmark to specifically label primary neural stem cells but we have also identified a key quality control step that determines their fate,” noted lead study investigator Fatih Semerci, Ph.D., a postdoctoral researcher in Dr. Maletic-Savatic’s lab. “Lunatic fringe allows neural stem cells to decide whether to stay dormant or not and, once they start to divide, whether to continue or to stop.”

The authors believe that their findings will have far-reaching implications on the field of neurogenesis since  age-related mental decline and psychiatric disorders such as anxiety and depression have been associated with a reduced ability to generate new neurons in the hippocampus—the center of learning and memory. Adult hippocampal neurogenesis has garnered significant interest in the past several years, as new targets could result in novel therapies for a variety of neurological disorders.