Adult hippocampal neurogenesis contributes to the hippocampal circuit's role in cognitive functioning. New neurons are generated from hippocampal neural stem cells (NSCs) throughout life, but their generation is substantially diminished in aged animals due to a decrease in NSC proliferation. Because acetylcholine (ACh) is an important neurotransmitter released in the hippocampus during learning and exercise that is known to decrease with aging, we investigated whether aged NSCs can respond to ACh. In this study, we found that cholinergic stimulation has a positive effect on NSC proliferation in both young adult (8-12 weeks old) and aged mice (>2 years old). In fresh hippocampal slices, we observed a rapid calcium increase in NSCs in the dentate gyrus after muscarinic cholinergic stimulation, in both age groups. Furthermore, we found that the exercise-induced promotion of aged NSC proliferation was abrogated by the specific lesioning of the septal cholinergic system. In turn, cholinergic activation by either eserine (physostigmine) or donepezil treatment promoted the proliferation of NSCs in aged mice. These results indicate that NSCs respond to cholinergic stimulation by proliferating in aged animals. Physiological and/or pharmacological cholinergic stimulation(s) may ameliorate cognitive decline in aged animals, by supporting adult hippocampal neurogenesis.
Di-and trimethylation of lysine 27 on histone H3 (H3K27me2/3) is an important gene repression mechanism. H3K27me2/3-specific demethylase, Jmjd3, was expressed in the inner nuclear layer during late retinal development. In contrast, H3K27 methyltransferase, Ezh2, was highly expressed in the embryonic retina but its expression decreased rapidly after birth. Jmjd3 loss of function in the developing retina resulted in failed differentiation of PKC-positive bipolar cell subsets (rod-ON-BP) and reduced transcription factor Bhlhb4 expression, which is critical for the differentiation of rod-ON-BP cells. Overexpression of Bhlhb4, but not of other BP cell-related genes, such as transcription factors Neurod and Chx10, in Jmjd3-knockdown retina rescued loss of PKC-positive BP cells. Populations of other retinal cell subsets were not significantly affected. In addition, proliferation activity and apoptotic cell number during retinal development were not affected by the loss of Jmjd3. Levels of histone H3 trimethyl Lys27 (H3K27me3) in the Bhlhb4 locus were lower in Islet-1-positive BP cells and amacrine cells than in the Islet-1-negative cell fraction. The Islet-1-negative cell fraction consisted mainly of photoreceptors, suggestive of lineage-specific demethylation of H3K27me3 in the Bhlhb4 locus. We propose that lineage-specific H3K27me3 demethylation of critical gene loci by spatiotemporal-specific Jmjd3 expression is required for appropriate maturation of retinal cells.histone methylation | progenitor | interneuron
In the retina, both neurons and glia differentiate from a common progenitor population. CD44 cell surface antigen is a hyaluronic acid receptor expressed on mature Mü ller glial cells. We found that in the developing mouse retina, expression of CD44 was transiently observed at or around birth in a subpopulation of c-kit-positive retinal progenitor cells. During in vitro culture, purified CD44/c-kit-positive retinal progenitor cells exclusively differentiated into Mü ller glial cells and not into neurons, suggesting that CD44 marks a subpopulation of retinal progenitor cells that are fated to become glia. Overexpression of CD44 inhibited the extension of processes by the neural retina (Rich et al. 1995), and protecting neurons from damage (Garcia and Vecino 2003). Furthermore, they act as neural progenitors to regenerate neurons in response to acute damage, especially in lower vertebrates (Dyer and Cepko 2000;Ooto et al. 2004;Karl et al. 2008;Osakada et al. 2008). As in the brain, Müller glial cells are thought to differentiate along with neurons from a common progenitor in the retina (Cepko 1993 (Furukawa et al. 1997;Hojo et al. 2000). However, known markers of glial cell lineages -brain glial markers included -seem to expressed relatively late in glial differentiation. Therefore, identification of early as well as cell surface markers would greatly facilitate the elucidation of mechanisms governing neuron-glia cell fate decisions. CD44 is a widely expressed transmembrane glycoprotein and cell surface receptor for hyaluronic acid (HA) (Ponta et al. 2003). It is thought to mediate cell migration, adhesion, tissue differentiation, and cancer metastasis. Through its relatively long intracellular domain, HA-CD44 interactions stimulate Rac1 signaling, leading to cytoskeletal effects and cell migration in astrocytes (Ponta et al. 2003). Roles for HA and CD44 have been suggested in neural systems. HA is one of the major glycosaminoglycans in the extracellular matrix and plays important roles in morphogenesis, remodeling, and integrity of the CNS. In the uninjured CNS, expression of CD44 is restricted to astrocytes in the white matter. In the retina in an injured or degenerating condition, expression of CD44 has been observed (Kuhrt et al. 1997;Chaitin and Brun-Zinkernage 1998). Localization of CD44 to Müller cell apical microvilli has been shown by immunostaining in normal mature rodent retina (Chaitin et al. 1994;Chaitin and Brun-Zinkernage 1998). However, its expression in developing retina has not been reported before. We found that CD44 was transiently expressed in developing mouse retina at around the P1 stage. CD44-labeled retinal cells were fated to differentiate into Müller glial cells, suggesting that CD44 labels the subset of retinal progenitor cells that becomes Müller glial cells. Experimental proceduresMice and reagents Enhanced green fluorescent protein (EGFP) transgenic mice, which express the EGFP gene ubiquitously via the Cytomegalovirus early enhancer element and chicken beta-actin promoter, w...
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