In today’s Nature, Fred Gage, from The Salk Institute, La Jolla, California, and colleagues report that Wnt signaling plays an important role in adult hippocampal neurogenesis. Ever since it turned out that adult neurogenesis does take place in the mammalian brain, scientists have raced to find ways to encourage new neurons to take over from old, dying, or damaged cells. The potential benefits this might bring to those suffering from neurodegenerative disorders, such as Alzheimer disease, are enormous. Unfortunately, the prospects for replacing neurons in this fashion look fairly bleak at present. Several obstacles must be cleared. First and foremost, neurogenesis only takes place in two specific regions of the brain, the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus, so to replace cells in the lobes of the cortex, for example, new neurons would have to be persuaded to trek from their rightful birthplace. This brings us to the second major problem. Because the neurogenesis process—including progenitor proliferation, differentiation, cell survival, and migration—is still a bit of a mystery, manipulating it is a tall order.
But little by little researchers are building a better picture of adult neurogenesis, and the present study by joint first authors Dieter-Chichung Lie—also at the Institute of Developmental Genetics, Munich, Germany—Sophia Colarmarino, and coworkers, adds a piece to the puzzle.
Wnts are secretory proteins involved in regulating development and cell proliferation (many are proto-oncogenes). There are 15 different Wnt signaling molecules in the human genome (called after the founding members, int-1 in mice and wingless in fruit flies) and ablating many of these genes leads to death at the embryonic stage. While the signaling pathways are thought to be particularly important for development of the embryonic central nervous system, there have also been hints that Wnt signaling is involved in adult neurogenesis, too (see ARF related news story). The current findings establish that connection.
Lie, Colamarino, and colleagues found that Wnt3 is expressed in close proximity to the subgranular zone in the hippocampus. More importantly, Wnt/β-catenin signaling is alive and kicking in that region, also. Activating the β-catenin transcription factor is one of the major ways in which Wnt molecules can influence gene regulation. Armed with this information, the authors tested the role of Wnts directly. To do this, they inhibited Wnt signaling in a co-culture system of adult hippocampal progenitors and adult hippocampal astrocytes because Gage and colleagues previously showed that astrocytes stimulate neurogenesis from adult neural stem cells (see ARF related news story). The authors found that if the Wnt pathway was blocked, then the number of progenitors that differentiated into neurons (as judged by abundance of the immature neuron marker doublecortin) shrank by about 60 percent. They also confirmed the β-catenin role by transfecting progenitors with dominant-negative variants of the β-catenin co-factors TCF and LEF. These reduced doublecortin expression by about 50 percent. In addition, when the investigators overexpressed Wnt3 in progenitors, they found a fivefold increase in the number of cells differentiating into neurons.
The findings suggest that Wnt3/β-catenin signaling is sufficient, though not essential, to enhance neurogenesis in hippocampal progenitor cultures. They found similar results in in-vivo experiments. When adult BATGAL mice were injected with bromodeoxyuridine (BrdU), which only gets incorporated into proliferating cells, they found that BrdU labeling and β-catenin signaling went hand-in-hand in the subgranular zone. Also, using lentiviruses to deliver and express various proteins in brain cells (Wnt3-negative mice die in utero), the authors confirmed that a dominant-negative Wnt reduced the number of cells incorporating BrdU or expressing doublecortin, and that activating Wnt signaling had the opposite effect.
All told, the experiments indicated that Wnt signaling, and particularly Wnt3 and the β-catenin pathway, play an important role in adult neurogenesis. In this regard, Wnt joins a small, elite group of signaling molecules, including sonic hedgehog (see ARF related news story), brain-derived growth factor (see Lee et al., 2002), and vascular endothelial growth factor (see Cao et al., 2004).
Wnt/β-catenin signaling pathways have also been linked to Alzheimer disease through interaction with presenilins, which form the catalytic core of the γ-secretase that processes amyloid-β precursor protein (see ARF Live Discussion). This, perhaps, reflects the complexities of the Wnt/β-catenin signaling pathways, which will hopefully be teased apart in detail in the coming years. In this regard, it is worth noting that not all Wnt3 mutations are lethal. A single point mutation (Q83X) is responsible for a rare and horrific human disease called Tetra-amelia, in which the fetus fails to develop limbs and also has multiple other developmental problems, including those of the central nervous system (see Niemann et al., 2004).—Tom Fagan
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- Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem. 2002 Sep;82(6):1367-75. PubMed.
- Cao L, Jiao X, Zuzga DS, Liu Y, Fong DM, Young D, During MJ. VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet. 2004 Aug;36(8):827-35. PubMed.
- Niemann S, Zhao C, Pascu F, Stahl U, Aulepp U, Niswander L, Weber JL, Müller U. Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. Am J Hum Genet. 2004 Mar;74(3):558-63. PubMed.
- Lie DC, Colamarino SA, Song HJ, Désiré L, Mira H, Consiglio A, Lein ES, Jessberger S, Lansford H, Dearie AR, Gage FH. Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005 Oct 27;437(7063):1370-5. PubMed.