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

Stanford University, United States of America
PLoS Biology (Impact Factor: 11.77). 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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    • "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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    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
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    • "The figures are organized according to both the species and the age, showing first those for the mouse and then those for the chicken, and within each species showing first those of early embryonic stages, followed by intermediate stages and finally those for late stages. For comparative purposes we also included published data on Prox1 in mouse in Table 1 (Zhou et al., 2004; Lavado et al., 2010, and the Allen Developing Mouse Brain Atlas). To assist in the distinction of the medial pallial ventricular sector from other pallial sectors, we also analyzed Lhx5 at early developmental stages in mouse and chicken (Tables 1, 2). "
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    ABSTRACT: We carried out a study of the expression patterns of seven developmental regulatory genes (Lef1, Lhx2, Lhx9, Lhx5, Lmo3, Lmo4, and Prox1), in combination with topological position, to identify the medial pallial derivatives, define its major subdivisions, and compare them between mouse and chicken. In both species, the medial pallium is defined as a pallial sector adjacent to the cortical hem and roof plate/choroid tela, showing moderate to strong ventricular zone expression of Lef1, Lhx2, and Lhx9, but not Lhx5. Based on this, the hippocampal formation (indusium griseum, dentate gyrus, Ammon's horn fields, and subiculum), the medial entorhinal cortex, and part of the amygdalo-hippocampal transition area of mouse appeared to derive from the medial pallium. In the chicken, based on the same position and gene expression profile, we propose that the hippocampus (including the V-shaped area), the parahippocampal area (including its caudolateral part), the entorhinal cortex, and the amygdalo-hippocampal transition area are medial pallial derivatives. Moreover, the combinatorial expression of Lef1, Prox1, Lmo4, and Lmo3 allowed the identification of dentate gyrus/CA3-like, CA1/subicular-like, and medial entorhinal-like comparable sectors in mouse and chicken, and point to the existence of mostly conserved molecular networks involved in hippocampal complex development. Notably, while the mouse medial entorhinal cortex derives from the medial pallium (similarly to the hippocampal formation, both being involved in spatial navigation and spatial memory), the lateral entorhinal cortex (involved in processing non-spatial, contextual information) appears to derive from a distinct dorsolateral caudal pallial sector.
    Frontiers in Neuroanatomy 07/2014; 8:59. DOI:10.3389/fnana.2014.00059 · 4.18 Impact Factor
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    • "These cells are readily labeled by a short BrdU pulsechase paradigm and express Nestin and Sox2, but not GFAP, Hes5, or BLBP (Lugert et al., 2010). Although there is a suggestion that quiescent radial glia-like and nonradial glial precursors are lineagerelated (Lavado et al., 2010), direct evidence demonstrating that removal of radial glia-like precursors also results in a complete loss of the nonradial glial precursor cell population is currently lacking. Much of the functional characterization of stem and precursor populations has come from in vitro studies utilizing the neurosphere assay (Bull and Bartlett, 2005; Walker et al., 2008; Jhaveri et al., 2010). "
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    ABSTRACT: Resident populations of stem and precursor cells drive the production of new neurons in the adult hippocampus. Recent discoveries have highlighted that a large proportion of these precursor cells are in fact quiescent and can be activated by distinct neuronal activity under both normal physiological and pathological conditions. As growing evidence indicates that newborn neurons play a critical role in cognitive functions such as learning and memory and in mood regulation, it is paramount that we obtain a better understanding of how the reservoirs of stem and precursor cells are maintained and activated. In this review, we critically examine the roles of key molecular mechanisms that have been shown to regulate hippocampal precursor cells, especially their activation. We believe that understanding the mechanistic details of the activity-driven regulation of precursor cells will equip us with the ability to develop tailored strategies to trigger the generation of new neurons, thereby improving the functional outcomes in various neurological and psychiatric conditions.
    Developmental Neurobiology 07/2012; 72(7):1044-58. DOI:10.1002/dneu.22027 · 4.19 Impact Factor
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