Article

Prox1 Is Required for Granule Cell Maturation and Intermediate Progenitor Maintenance During Brain Neurogenesis

Stanford University, United States of America
PLoS Biology (Impact Factor: 9.34). 08/2010; 8(8). DOI: 10.1371/journal.pbio.1000460
Source: PubMed

ABSTRACT

Author Summary
In the brain, the hippocampus has a crucial role in learning and memory. In mammals, neurogenesis (the birth of new neurons) occurs in the dentate gyrus region of the hippocampus throughout adulthood, and this activity is thought to be the basis for the acquisition of new memories. In this study we describe for the first time the functional roles of the transcription factor Prox1 during brain development and adult neurogenesis. We demonstrate that in mammals, Prox1 is required for the differentiation of granule cells during dentate gyrus development. We also show that conditional inactivation of Prox1 results in the absence of specific intermediate progenitors in the subgranular zone of the dentate gyrus, which prevents adult neurogenesis from occurring. This is the first report showing blockade of adult neurogenesis at the level of progenitor cells. Next, we demonstrate that in the absence of Prox1-expressing intermediate progenitors, the stem cell population of the subgranular zone becomes depleted. Further, we show that Prox1-expressing intermediate progenitors are required for adult neural stem cell self-maintenance in the subgranular zone. Finally, we demonstrate that Prox1 ectopic expression induces premature granule cell differentiation in the subgranular zone. Therefore, our results identify a previously unknown non-cell autonomous feedback mechanism that links adult stem cell self-maintenance with neuronal differentiation in the dentate gyrus and could have important implications for neurogenesis in other brain regions.

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    • "Les astrocytes jouentégalementjouentégalement un rôle essentiel dans la différenciation neuronale des progéniteurs ainsi que dans l'intégration des nouveaux neurones (Song et al., 2002 ;Ma et al., 2005). Concernant les facteurs spécifiques participantàparticipant`participantà l'environnement optimal de la niche neurogénique, on peut citer les g` enes Prospero homeobox protein 1 (Prox-1) et SRY box-containing gene-2 qui jouent un rôle dans le maintien des cellules progénitrices (Lavado et al., 2010 ;Mu et al., 2012), les facteurs Sonic hedgehog, Brain derived neurotrophic factor (BDNF), Insulin-like growth factor 2, la protéine disrupted-inschizophrenia 1 ou encore le régulateurrégulateurépigénétique Growth arrest and DNA damage qui sont nécessaires nécessairesà la prolifération des cellules progénitrices (pour re- vueMu et al., 2010 ;Benarroch, 2013). Le GABA joué egalement un rôle essentiel au sein de la niche dans le taux de prolifération des cellules progénitrices (Duveau et al., 2011 ;Giachino et al., 2014). "
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    ABSTRACT: A defining characteristic of the brain is its remarkable capacity to undergo activity-dependent functional and structural remodelling via mechanisms of plasticity that form the basis of our capacity to encode and retain memories. The prevailing model of how our brain stores new information about relationships between events or new abstract constructs suggests it resides in activity-driven modifications of synaptic strength and remodelling of neural networks brought about by cellular and molecular changes within the neurons activated during learning. To date, the idea that a form of activity-dependent synaptic plasticity known as long-term potentiation, or LTP, and the associated synaptic growth play a central role in the laying down of memories has received considerable support. Beyond this mechanism of plasticity at the synapse, adult neurogenesis, i.e. the birth and growth of new neurons, is another form of neural plasticity that occurs continuously in defined brain regions such as the dentate gyrus of the hippocampus. Here, based on work in the hippocampus, we review the processes and mechanisms of the generation and selection of new neurons in the adult brain and the accumulating evidence that supports the idea that this form of neural plasticity is essential to store and lead to retrievable hippocampal-dependent memories.
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    • "Indeed, NeuroD1 or Prox1 overexpression promotes neuronal differentiation of neural stem cells in vitro (Hsieh et al. 2004; Gao et al. 2009; Karalay et al. 2011). Conditional ablation of NeuroD1 as well as deletion of Prox1 via conditional ablation or knockdown from the hippocampal neurogenic lineage reduced the generation of DCX-positive immature neurons (Gao et al. 2009; Lavado et al. 2010; Karalay et al. 2011). Whether the reduction in neurogenesis was the consequence of impaired neuronal fate determination or of another mechanism remained to be determined. "
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    ABSTRACT: Adult-generated dentate granule neurons have emerged as major contributors to hippocampal plasticity. Newneurons are generated fromneural stem cells through a complex sequence of proliferation, differentiation, and maturation steps. Development of the new neuron is dependent on the precise temporal activity of transcription factors, which coordinate the expression of stage-specific genetic programs. Here, we review current knowledge in transcription factor-mediated regulation of mammalian neural stem cells and neurogenesis and will discuss potential mechanisms of how transcription factor networks, on one hand, allow for precise execution of the developmental sequence and, on the other hand, allow for adaptation of the rate and timing of adult neurogenesis in response to complex stimuli. Understanding transcription factor-mediated control of neuronal development will provide new insights into the mechanisms underlying neurogenesis-dependent plasticity in health and disease. © 2015 Cold Spring Harbor Laboratory Press. All rights reserved.
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    • "Considering that Sox2 is a reliable marker of embryonic NSCs, essential for maintenance of their self-renewal and neurogenic ability (Thiel, 2013), and Prox1 is a postmitotic factor, required for granule cells maturation and cell fate determination (Lavado et al., 2010; Iwano et al., 2012), it can be concluded that differentiation and maturation of newborn granule cells occur strictly within the proliferative PL's zone, the SGZ and the extending GCL, and that proliferative cells migrating there are purely embryonic NSCs. "
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