Prox1 is required for granule cell maturation and intermediate progenitor maintenance during brain neurogenesis.

Department of Genetics & Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
PLoS Biology (Impact Factor: 11.77). 08/2010; 8(8). DOI: 10.1371/journal.pbio.1000460
Source: PubMed

ABSTRACT The dentate gyrus has an important role in learning and memory, and adult neurogenesis in the subgranular zone of the dentate gyrus may play a role in the acquisition of new memories. The homeobox gene Prox1 is expressed in the dentate gyrus during embryonic development and adult neurogenesis. Here we show that Prox1 is necessary for the maturation of granule cells in the dentate gyrus during development and for the maintenance of intermediate progenitors during adult neurogenesis. We also demonstrate that Prox1-expressing intermediate progenitors are required for adult neural stem cell self-maintenance in the subgranular zone; thus, we have identified a previously unknown non-cell autonomous regulatory feedback mechanism that controls adult neurogenesis in this region of the mammalian brain. Finally, we show that the ectopic expression of Prox1 induces premature differentiation of neural stem cells.

  • [Show abstract] [Hide abstract]
    ABSTRACT: In the mammalian hippocampus, canonical Wnt signals provided by the microenvironment regulate the differentiation of adult neural stem cells (NSCs) toward the neuronal lineage. Wnts are part of a complex and diverse set of signaling pathways and the role of Wnt/Planar cell polarity (PCP) signaling in adult neurogenesis remains unknown. Using in vitro assays on differentiating adult NSCs, we identified a transition of Wnt signaling responsiveness from Wnt/β-catenin to Wnt/PCP signaling. In mice, retroviral knockdown strategies against ATP6AP2, a recently discovered core protein involved in both signaling pathways, revealed that its dual role is critical for granule cell fate and morphogenesis. We were able to confirm its dual role in neurogenic Wnt signaling in vitro for both canonical Wnt signaling in proliferating adult NSCs and non-canonical Wnt signaling in differentiating neuroblasts. Although LRP6 appeared to be critical for granule cell fate determination, in vivo knockdown of PCP core proteins FZD3 and CELSR1-3 revealed severe maturational defects without changing the identity of newborn granule cells. Furthermore, we found that CELSR1-3 control distinctive aspects of PCP-mediated granule cell morphogenesis with CELSR1 regulating the direction of dendrite initiation sites and CELSR2/3 controlling radial migration and dendritic patterning. The data presented here characterize distinctive roles for Wnt/β-catenin signaling in granule cell fate determination and for Wnt/PCP signaling in controlling the morphological maturation of differentiating neuroblasts. Copyright © 2015 the authors 0270-6474/15/354983-16$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 03/2015; 35(12):4983-98. DOI:10.1523/JNEUROSCI.4130-14.2015 · 6.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Newborn granule neurons generated from neural progenitor cells (NPCs) in the adult hippocampus play a key role in spatial learning and pattern separation. However, the molecular mechanisms that control activation of their neurogenic program remain poorly understood. Here, we report a novel function for the pluripotency factor sex-determining region Y (SRY)-related HMG box 2 (SOX2) in regulating the epigenetic landscape of poised genes activated at the onset of neuronal differentiation. We found that SOX2 binds to bivalently marked promoters of poised proneural genes [neurogenin 2 (Ngn2) and neurogenic differentiation 1 (NeuroD1)] and a subset of neurogenic genes [e.g., SRY-box 21 (Sox21), brain-derived neurotrophic factor (Bdnf), and growth arrest and DNA-damage-inducible, beta (Gadd45b)] where it functions to maintain the bivalent chromatin state by preventing excessive polycomb repressive complex 2 activity. Conditional ablation of SOX2 in adult hippocampal NPCs impaired the activation of proneural and neurogenic genes, resulting in increased neuroblast death and functionally aberrant newborn neurons. We propose that SOX2 sets a permissive epigenetic state in NPCs, thus enabling proper activation of the neuronal differentiation program under neurogenic cue.
    Proceedings of the National Academy of Sciences 03/2015; 112(15). DOI:10.1073/pnas.1421480112 · 9.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The term “adult neurogenesis” describes the continuous generation of cohorts of new neurons in some discrete regions of the adult brain, such as the dentate gyrus of the hippocampus. Adult hippocampal neurogenesis (ahNG) has been shown as relevant for typical functions of this brain areal (e.g. memory consolidation), but also influences social behavior and has medical relevance. The exact dynamics of this neuronal development are still unknown, as are psychosocial impacts on this process. To analyze the temporal pattern of ahNG and quantify the development of the new neurons we analyzed the relative and absolute numbers of cells in all known stages of the neural differentiation, from stem cell phase towards neurons, in mice at different time points after BrdU injection. BrdU permanently labels cells during S-phase of the cell cycle and enabled us to follow a cohort of new cells over time, thus, here a pseudo-longitudinal study was performed. Subsequently, first studies on the relation between social factors and ahNG in mammals are presented. Regulation of the neuronal development is related to, and dependent on inputs from the outer environment. A connection between ahNG and social environment has been demonstrated previously, but detailed information on the altered differentiation process is missing. In the first part of this thesis I present detailed information on the progression of distinct cell types through the differentiation process of ahNG. Transitions over time are observed allowing the estimation of cell cycle length (CCL) for each cell type involved in ahNG. I found, that the individual cell types are more flexible than assumed before. In the second part, I investigate the impact of social housing, (behavioral relevant) auditori stimuli and stress on ahNG. While the positive factors were applied to healthy subjects, I used the stress paradigm in the GR+/- mice model of depression. Flexible adaptations of different stages in ahNG were also found in these studies on social factors. Each single stimulator affected individual differentiation stages in characteristic ways. While group size, music, silence and pup calls increase BrdU cell counts in proliferation analyses, with distinct effects on each mitotic differentiation stage, does only silence increase survival of new neurons. In the GR+/- mouse model I found decreased ahNG, without any effect on the proportion of neurogenesis or gliogenesis. Based on the information obtained about the dynamics of ahNG a new, innovative model of ahNG is proposed, pushing type-1 and type-2a cells in the center of attention, while diminishing the weight of type-3 cells for the process of differentiation. Type-1 cells, previously assumed as origin of neurogenesis in the hippocampus, are here hypothesized as safeguard of the system, while type-2a cells, highly proliferative, giving rise to gliogenesis and neurogenesis, are hypothesized as the origin of ahNG under normal, healthy conditions. The additional studies give some indications for changes of the model caused by different social factors. The aim is to draw attention to the importance and impact of social environment on adult neurogenesis, brain plasticity and mental health. Thus, future studies will focus more on the promising field of ahNG.
    01/2012, Degree: PhD, Supervisor: Gerd Kempermann