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

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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. 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.