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.

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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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    • "Tbr2+ cells/mm3 dentate gyrus; ANOVA F(2,23) = 5.207, P = 0.014) compared to both wild-type controls (post-hoc Bonferroni p<0.05) and Disc1100P/100P mutant mice (post-hoc Bonferroni p<0.05), demonstrating a general proliferation defect caused by the Q31L mutation. While the vast majority of Tbr2 immunopositive cells were restricted to the SGZ, we detected a few Tbr2+ cells in the hilus and dentate gyrus molecular layer irrespective of Disc1 genotype, which was detected in hippocampal sections in reports from other groups [20], [21]. This suggests that there are either a few undifferentiated progenitors normally residing in the granule cell layer, or that some postmitotic neurons retain Tbr2 activity. "
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    ABSTRACT: Disrupted in schizophrenia 1 (DISC1) is a risk factor for a spectrum of neuropsychiatric illnesses including schizophrenia, bipolar disorder, and major depressive disorder. Here we use two missense Disc1 mouse mutants, described previously with distinct behavioural phenotypes, to demonstrate that Disc1 variation exerts differing effects on the formation of newly generated neurons in the adult hippocampus. Disc1 mice carrying a homozygous Q31L mutation, and displaying depressive-like phenotypes, have fewer proliferating cells while Disc1 mice with a homozygous L100P mutation that induces schizophrenia-like phenotypes, show changes in the generation, placement and maturation of newly generated neurons in the hippocampal dentate gyrus. Our results demonstrate Disc1 allele specific effects in the adult hippocampus, and suggest that the divergence in behavioural phenotypes may in part stem from changes in specific cell populations in the brain.
    PLoS ONE 10/2014; 9(10):e108088. DOI:10.1371/journal.pone.0108088 · 3.23 Impact Factor
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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 · 3.54 Impact Factor
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