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


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.

Download full-text


Available from: Lionel Chow,

Click to see the full-text of:

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

8.58 MB

See full-text
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Cold Spring Harbor perspectives in biology 10/2015; 7(10):a018879. DOI:10.1101/cshperspect.a018879 · 8.68 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A bulk of evidence currently suggests that hippocampal formation is a heterogeneous brain structure. Most recent studies recognize a hippocampal pole (dorsal/septal or posterior in humans) which is primarily related with memory and learning processes, and another one (ventral/temporal or anterior in humans) which is linked with anxiety, affective or emotional processes. An intermediate region separating the two poles appears to have overlapping characteristics with its neighbors. The present chapter summarizes previously reported differences between septal and temporal dentate gyrus, a key component of the hippocampal circuitry, and provides new information on the segmental variation of the dentate gyrus. Data on the cellular (neuronal and glial) composition of the dentate gyrus are linked with the diverged embryonic origin and continuous cell generation capacity of the septal and temporal poles, septo-temporal molecular/genomic patterns are correlated with trends reported by connectivity (tracing) studies, and distinct characteristics of the two poles in the healthy and the diseased brain are examined together with their peculiar neurochemical and vascularization patterns in order to i. provide an explanatory framework for the understanding of the segmental hippocampal functional and behavioral specialization, and ii. highlight the need for thorough and detailed knowledge of all possible parameters which may allow unlocking of the hippocampal dysfunction. No part of this digital document may be reproduced, stored in a retrieval system or transmitted commercially in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.
    Dentate Gyrus, Edited by Zackery Lowes, 01/2015: chapter 5: pages 137-198; Nova Science Publishers Inc.., ISBN: 978-1-63463-371-0
  • Source
    • "Conditional deletion of Prox1 in the adult DG impairs the proliferation, survival and differentiation of DG IPCs (Lavado et al., 2010). Even though Prox1 is not expressed in NSCs, the loss of Jagged1- expressing IPCs results in the exhaustion of the NSC pool, due to a decrease in Notch signaling in the stem cells (Lavado et al., 2010). Both Tbr2 and Prox1 conserve the same roles in the generation of granule cells during embryonic/postnatal hippocampal development and in the adult DG. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurogenesis persists in adult mammals in specific brain areas, known as neurogenic niches. Adult neurogenesis is highly dynamic and is modulated by multiple physiological stimuli and pathological states. There is a strong interest in understanding how this process is regulated, particularly since active neuronal production has been demonstrated in both the hippocampus and the subventricular zone (SVZ) of adult humans. The molecular mechanisms that control neurogenesis have been extensively studied during embryonic development. Therefore, we have a broad knowledge of the intrinsic factors and extracellular signaling pathways driving proliferation and differentiation of embryonic neural precursors. Many of these factors also play important roles during adult neurogenesis, but essential differences exist in the biological responses of neural precursors in the embryonic and adult contexts. Because adult neural stem cells (NSCs) are normally found in a quiescent state, regulatory pathways can affect adult neurogenesis in ways that have no clear counterpart during embryogenesis. BMP signaling, for instance, regulates NSC behavior both during embryonic and adult neurogenesis. However, this pathway maintains stem cell proliferation in the embryo, while it promotes quiescence to prevent stem cell exhaustion in the adult brain. In this review, we will compare and contrast the functions of transcription factors (TFs) and other regulatory molecules in the embryonic brain and in adult neurogenic regions of the adult brain in the mouse, with a special focus on the hippocampal niche and on the regulation of the balance between quiescence and activation of adult NSCs in this region.
    Frontiers in Cellular Neuroscience 11/2014; 8:396. DOI:10.3389/fncel.2014.00396 · 4.29 Impact Factor
Show more