Abstract
The specification and differentiation of dentate gyrus granule neurons in the hippocampus require temporally and spatially coordinated actions of both intrinsic and extrinsic molecules. The basic helix-loop-helix transcription factor Neurogenin2 (Ngn2) and NeuroD1 are key regulators in these processes. Based on existing classification, we analyzed the molecular events occurring during hippocampal neurogenesis, primarily focusing on juvenile animals. We found that Ngn2 is transiently expressed by late type-2a amplifying progenitors. The Ngn2 progenies mature into hippocampal granule neurons. Interestingly, the loss of Ngn2 at early stages of development leads to a robust reduction in neurogenesis, but does not disturb granule neuron maturation per se. We found that the role of Ngn2 is to maintain progenitors in an undifferentiated state, allowing them to amplify prior to their maturation into granule neurons upon NeuroD1 induction. When we overexpressed Ngn2 and NeuroD1 in vivo, we found NeuroD1 to exhibit a more pronounced neuron-inductive effect, leading to granule neuron commitment, than that displayed by Ngn2. Finally, we observed that all markers expressed during the transcriptional control of hippocampal neurogenesis in rodents are also present in the human hippocampus. Taken together, we demonstrate a critical role of for Ngn2 and NeuroD1 in controlling neuronal commitment and hippocampal granule neuroblast formation, both during embryonic development and in post-natal hippocampal granule neurogenesis.
Highlights
Neurons are born during development of the central nervous system, but neurogenesis continues into adulthood
In both rodent and human adult brain, neurogenesis is active in two distinct zones of the forebrain: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) [1,2,3,4,5]
We first analyzed in detail the chronology of expression of different transcription factors and cell-specific markers during DG granule neuron formation and correlated our findings to the previously established classification of adult hippocampal neurogenesis [3]
Summary
Neurons are born during development of the central nervous system, but neurogenesis continues into adulthood. In both rodent and human adult brain, neurogenesis is active in two distinct zones of the forebrain: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) [1,2,3,4,5]. The paired-box homeodomain transcription factor Pax and the bHLH transcription factors Ngn and NeuroD1 are important when cells acquire a pan-neuronal character and a specific neuronal subtype [9,10]. In the absence of Ngn, NeuroD1 can still be activated and neuronal differentiation can still take place [20]. This has led to the idea that the primary role of Ngn is not to direct neuronal differentiation
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