DNA Methyltransferase 1 Is Indispensable for Development of the Hippocampal Dentate Gyrus

Abstract

Development of the hippocampal dentate gyrus (DG) in the mammalian brain is achieved through multiple processes during late embryonic and postnatal stages, with each developmental step being strictly governed by extracellular cues and intracellular mechanisms. Here, we show that the maintenance DNA methyltransferase 1 (Dnmt1) is critical for development of the DG in the mouse. Deletion of Dnmt1 in neural stem cells (NSCs) at the beginning of DG development led to a smaller size of the granule cell layer in the DG. NSCs lacking Dnmt1 failed to establish proper radial processes or to migrate into the subgranular zone, resulting in aberrant neuronal production in the molecular layer of the DG and a reduction of integrated neurons in the granule cell layer. Interestingly, prenatal deletion of Dnmt1 in NSCs affected not only the developmental progression of the DG but also the properties of NSCs maintained into adulthood: Dnmt1-deficient NSCs displayed impaired neurogenic ability and proliferation. We also found that Dnmt1 deficiency in NSCs decreased the expression of Reelin signaling components in the developing DG and increased that of the cell cycle inhibitors p21 and p57 in the adult DG. Together, these findings led us to propose that Dnmt1 functions as a key regulator to ensure the proper development of the DG, as well as the proper status of NSCs maintained into adulthood, by modulating extracellular signaling and intracellular mechanisms.

Prenatal deletion ofDNA methyltransferase 1in neural stem cells impairs neurogenesis and causes anxiety-like behavior in adulthood

“…We have previously reported that the enzyme DMNT1 is highly expressed in NSCs in both embryonic and adult brains. 19,36 However, in contrast to the results obtained for prenatal deletion, loss of Dnmt1 in NSCs during the adult stage impairs neither proliferation nor neuronal differentiation of NSCs. 16 Furthermore, upregulation of GFAP expression and activation of microglia in the adult brain were not observed in mice lacking Dnmt1 in NSCs (data not shown).…”

“…Mice that had undergone prenatal deletion of Dnmt1 were allowed to mature until adulthood and displayed no obvious defects in body size, brain structure, or brain weight. 19 Previously, we reported that prenatal deletion of Dnmt1 impairs adult neurogenesis in the DG. 19 However, the influence of such deletion on adult neurogenesis in the SVZ remains to be examined.…”

“…19 Previously, we reported that prenatal deletion of Dnmt1 impairs adult neurogenesis in the DG. 19 However, the influence of such deletion on adult neurogenesis in the SVZ remains to be examined. Therefore, in the present study, we further investigated the effects of prenatal Dnmt1 deletion on adult neurogenesis in both neurogenic niches, placing particular emphasis on adult neurogenesis in the SVZ.…”

“…17 Accumulating evidence has also indicated that epigenetic regulation provides significant contributions to both cortical and DG development. 18,19 Previously, we observed that prenatal exposure to valproic acid (VPA) impairs neurogenesis and hippocampus-dependent learning and memory even into adulthood. 20 Furthermore, we have also reported that prenatal deletion of Dnmt1 in NSCs impairs DG development by attenuating neurogenesis in the DG.…”

“…20 Furthermore, we have also reported that prenatal deletion of Dnmt1 in NSCs impairs DG development by attenuating neurogenesis in the DG. 19 The results of these studies have raised the possibility that appropriate epigenetic regulation during development of the prenatal brain is critical for the establishment and maintenance of proper niche environments and NSCs in adulthood. Therefore, in the present study, we aimed to investigate the role of Dnmt1 in DG neurogenesis by examining the behavior of adult mice in which the Dnmt1 gene had been deleted during a late prenatal stage, and by assessing the effects of this mutation on brain structure.…”