Adult Neurogenesis—A Win Wnt Situation?

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

Comments

  1. The identification of Wnt signaling as a major player in the regulation of adult hippocampal neurogenesis is probably one of the most important scientific discoveries of this year. Gage´s lab not only opens an exciting new avenue for the understanding of the environmental signals that influence adult neurogenesis, but also improves prospects for potential therapeutic benefits of stem cell technology in brain aging and Alzheimer disease.

    For AD patients, we need a “pathway” that increases the neurogenic potential of adult brain cells and at the same time is able to protect neurons from the toxic effects of the amyloid-β peptide (Aβ). Previous studies from our lab indicate that activation of Wnt signaling prevents Aβ neurotoxicity in hippocampal neurons (De Ferrari et al., 2003; Quintanilla et al., 2005). That astrocyte-derived Wnts and Wnt/β-catenin signaling in adult hippocampal stem/progenitor cells (AHPs) are substantial contributors to the neuronal differentiation of AHPs induced by hippocampal astrocytes is very appealing for AD. A consistent feature around the amyloid deposits is the appearance of reactive astrocytes, which may release cytokines. It is therefore possible that in AD patients, a controlled release of Wnt ligands or Wnt pathway activation (i.e., GSK-3β inhibitors) would eventually help to induce neuronal survival and cell fate instruction from stem/progenitor cells.

    For our lab, it is rewarding that Wnt3 became the ligand involved in the regulation of adult hippocampal neurogenesis, because it was the same Wnt ligand that we found to prevent Aβ neurotoxicity in hippocampal neurons (Alvarez et al., 2004). Fred Gage´s study on the effect of the canonical Wnt pathway on adult neurogenesis offers an opportunity for AD researchers to be more aware of the potential implications of the relationship between Wnt signaling and AD.

    References:

    De Ferrari GV, Chacón MA, Barría MI, Garrido JL, Godoy JA, Olivares G, Reyes AE, Alvarez A, Bronfman M, Inestrosa NC. Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils. Mol Psychiatry. 2003 Feb;8(2):195-208. PubMed.

    Quintanilla RA, Muñoz FJ, Metcalfe MJ, Hitschfeld M, Olivares G, Godoy JA, Inestrosa NC. Trolox and 17beta-estradiol protect against amyloid beta-peptide neurotoxicity by a mechanism that involves modulation of the Wnt signaling pathway. J Biol Chem. 2005 Mar 25;280(12):11615-25. PubMed.

    Alvarez AR, Godoy JA, Mullendorff K, Olivares GH, Bronfman M, Inestrosa NC. Wnt-3a overcomes beta-amyloid toxicity in rat hippocampal neurons. Exp Cell Res. 2004 Jul 1;297(1):186-96. PubMed.

    View all comments by Nibaldo Inestrosa

  2. The canonical Wnt signaling pathway has multiple roles in stem/progenitor cells. In embryonic stem cells, activation of Wnt promotes self-renewal and inhibits neural differentiation (1,2). In the central nervous system, Wnt3a is required for neural progenitor proliferation and hippocampal development (3). Wnt family members are also necessary for expanding neural crest progenitors (4). In contrast, Wnt/β-catenin promotes cell fate specification rather than progenitor cell expansion in the dorsal spinal cord (5) and in the developing cortex (6). Thus, the role of Wnt in stem/progenitor cells seems to depend both on the context and cell-intrinsic properties.

    Now, this paper provides a compelling piece of evidence about the role of Wnt signaling in the regulation of adult hippocampal neurogenesis. Part of the relevance of this finding relies on the fact that abnormalities of Wnt signaling are involved in brain diseases that might benefit from support of endogenous neurogenesis, such as cerebral ischemia (7) and Alzheimer disease (8,9).

    Nibaldo Inestrosa and coworkers first suggested that a loss of Wnt function is implicated in the pathophysiology of neuronal degeneration in AD (8). Accordingly, we have found that Dickkopf-1 (DKK-1), a negative modulator of the Wnt pathway, is induced in cultured neurons challenged with Aβ, as well as in degenerating neurons of AD brain (9). The induction of DKK-1 contributes to the pathological cascade activated by β-amyloid and particularly to tau hyperphosphorylation. We have suggested that DKK-1 antagonists or drugs that rescue the Wnt pathway acting downstream of the DKK-1 blockade are potential neuroprotective agents in AD. Based on Rusty Gage’s study, we can start thinking about the possibility that these drugs might also help to sustain neurogenesis in AD. However, we must consider that the feasibility of such a treatment could be influenced by a number of disease-related extracellular factors that may modify the response of progenitor cells to Wnt.

    References:

    Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med. 2004 Jan;10(1):55-63. PubMed.

    Aubert J, Dunstan H, Chambers I, Smith A. Functional gene screening in embryonic stem cells implicates Wnt antagonism in neural differentiation. Nat Biotechnol. 2002 Dec;20(12):1240-5. PubMed.

    Lee SM, Tole S, Grove E, McMahon AP. A local Wnt-3a signal is required for development of the mammalian hippocampus. Development. 2000 Feb;127(3):457-67. PubMed.

    Ikeya M, Lee SM, Johnson JE, McMahon AP, Takada S. Wnt signalling required for expansion of neural crest and CNS progenitors. Nature. 1997 Oct 30;389(6654):966-70. PubMed.

    Muroyama Y, Fujihara M, Ikeya M, Kondoh H, Takada S. Wnt signaling plays an essential role in neuronal specification of the dorsal spinal cord. Genes Dev. 2002 Mar 1;16(5):548-53. PubMed.

    Hirabayashi Y, Itoh Y, Tabata H, Nakajima K, Akiyama T, Masuyama N, Gotoh Y. The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development. 2004 Jun;131(12):2791-801. PubMed.

    Cappuccio I, Calderone A, Busceti CL, Biagioni F, Pontarelli F, Bruno V, Storto M, Terstappen GT, Gaviraghi G, Fornai F, Battaglia G, Melchiorri D, Zukin RS, Zukin S, Nicoletti F, Caricasole A. Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is required for the development of ischemic neuronal death. J Neurosci. 2005 Mar 9;25(10):2647-57. PubMed.

    De Ferrari GV, Inestrosa NC. Wnt signaling function in Alzheimer's disease. Brain Res Brain Res Rev. 2000 Aug;33(1):1-12. PubMed.

    Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller AJ, Caruso A, Storto M, Gaviraghi G, Terstappen GC, Nicoletti F. Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain. J Neurosci. 2004 Jun 30;24(26):6021-7. PubMed.

    View all comments by Agata Copani

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References

News Citations

  1. News Trio on Stem Cell Programming
  2. Astrocytes May Hold Key to Adult Neurogenesis
  3. Playing Sonic Hedgehog in the Hippocampus

Paper Citations

  1. 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.
  2. 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.
  3. 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.

Other Citations

  1. ARF Live Discussion

Further Reading

Primary Papers

  1. 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.

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