Summary: A new study published in eLife reports that lunatic fringe genes mediate a mechanism that preserves neural stem cells, allowing the adult brain to generate new neurons throughout life. The researchers say these findings have wide implications for understanding adult neurogenesis and hippocampal stem cell regulation.
Source: Baylor College of Medicine
Researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital have created a new mouse model that, for the first time, selectively labels primary neural stem cells (NSCs). Using this model, the team uncovered a feedback mechanism in which the descendants of neural stem cells influence the division and fate of their parent NSC. The results were published in eLife.
“Our initial goal was to identify a gene selectively expressed in primary neural stem cells. Starting from public expression databases, we evaluated roughly 750 candidate genes and, after careful and systematic analysis, identified Lunatic fringe (Lfng) as a selective marker of NSCs,” said Dr. Mirjana Maletić-Savatić, assistant professor of pediatrics and neurology at Baylor and Texas Children’s Hospital and the study’s senior author. “Discovering Lfng as a selective NSC marker led us to investigate its functional role within the Notch signaling pathway.”
Members of the Notch signaling pathway have previously been implicated in regulating stem cell fate across multiple animal models. Because Lfng modifies Notch receptors, its selective expression in NSCs suggested it could fine-tune Notch activity in the adult hippocampus, where new neurons are generated. Until now, the detailed mechanisms that tune Notch signaling in adult hippocampal neurogenesis were not fully understood.
Lunatic fringe supports a renewable brain
Maletić-Savatić and colleagues demonstrate that Lunatic fringe helps preserve the adult pool of NSCs so they can produce new neurons across the lifespan while maintaining an appropriate balance in neuron numbers. The researchers show that Lfng enables NSCs to respond differently to nearby cells expressing distinct Notch ligands, primarily Delta1 and Jagged1.
Neural stem cells and their progeny naturally form tight clusters, creating an ideal environment for direct cell-to-cell communication. The study found that when NSCs are surrounded by cells expressing Delta1, most NSCs remain in a quiescent or “stand-by” state, protected from random activation and unnecessary division. In contrast, contact with cells that express Jagged1 triggers NSC activation and division. Together, these opposing influences allow precise control over each NSC’s decision to remain dormant, enter the cell cycle, or differentiate—preventing excessive division and premature depletion of the stem cell pool.
“This mouse model is a major advance for neural stem cell biology because it gives us a reliable marker to label primary NSCs and reveals a crucial quality-control step that governs their behavior,” said Fatih Semerci, postdoctoral researcher in the Maletić-Savatić lab and lead author of the study. “Lunatic fringe helps NSCs decide whether to remain dormant, begin dividing, or stop dividing once activated.”
The implications of these findings reach beyond basic stem cell biology. Age-related cognitive decline and psychiatric conditions such as anxiety and depression have been linked to reduced hippocampal neurogenesis. Adult hippocampal neurogenesis is influenced by lifestyle and environmental factors—physical exercise and enriched environments boost neuron formation, while social isolation and depression can reduce it. Because adult neurogenesis affects learning, memory, and mood, understanding mechanisms that maintain and recruit NSCs could inform future therapeutic approaches for cognitive and mood disorders.
Additional contributors to this study include William Tin-Shing Choi, Aleksandar Bajic, Aarohi Thakkar, Juan Manuel Encinas, and Andrew Groves of Baylor College of Medicine; Frederic Depreux of Rosalind Franklin University of Medicine and Science; and Neil Segil of the University of Southern California.
Funding: This work was supported by the Nancy Chang Award and the CPRIT grant (RP130573CPRIT). Additional support came from Baylor College of Medicine core facilities (Microscopy, RNA In Situ Hybridization, and Neuropathology) funded in part by NIH Shared Instrumentation (1S10OD016167) and the NIH IDDRC grant (U54HD083092). The Cytometry and Cell Sorting Core contributed resources supported by NCRR grant S10RR024574, NIAID AI036211 and NCI P30CA125123.
Source: Graciela Gutierrez, Baylor College of Medicine
Image source: NeuroscienceNews.com image used for illustration and reported to be in the public domain.
Original research: Semerci F., Choi W.T.-S., Bajic A., Thakkar A., Encinas J.M., Depreux F., Segil N., Groves A.K., Maletić-Savatić M. “Lunatic fringe-mediated Notch signaling regulates adult hippocampal neural stem cell maintenance.” eLife. Published online July 12, 2017. DOI: 10.7554/eLife.24660
Lunatic fringe-mediated Notch signaling regulates adult hippocampal neural stem cell maintenance
Hippocampal neural stem cells integrate signals from multiple sources to balance quiescence and activation, with Notch signaling playing a central role in this regulation. The authors report that Lunatic fringe (Lfng), a key modifier of the Notch receptor, is selectively expressed in hippocampal NSCs. Lfng expressed in NSCs, together with Notch ligands Delta1 and Jagged1 produced by their progeny, shapes NSC recruitment, cell cycle length, and terminal fate. The study proposes a model in which Lfng-mediated Notch signaling allows direct communication between an NSC and its descendants so that progeny can send feedback to the “mother” cell and alter its cell cycle state. Lfng-mediated Notch signaling emerges as a critical regulator of NSC quiescence, division, and fate decisions.
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