Involvement of Granulin in Estrogen-Induced Neurogenesis in the Adult Rat Hippocampus

Abstract

Abstract. Recent studies have demonstrated the presence of neurogenesis in the adult mammalian hippocampus, and it has been suggested that estrogen and various growth factors influence the processes of adult neurogenesis. The present study assessed cell proliferation in the dentate gyrus and the mRNA expression levels of granulin, insulin-like growth factor-I (IGF-I), and brain-derived neurotrophic factor (BDNF) in the hippocampus 4 h after treatment with estradiol benzoate (EB) in 3-and 12-month old ovariectomized rats. At 3 months of age, mRNA expression of granulin precursor and cell proliferation were increased by EB treatment, although the mRNA expressions of IGF-I and BDNF remained unchanged. At 12 months of age, however, neither mRNA expression of the three genes nor cell proliferation in the dentate gyrus were affected by EB treatment. In addition, 17β-estradiol enhanced the proliferation of neural progenitor cells derived from hippocampal tissue of 3-month-old female rats in vitro; this was inhibited by neutralization of granulin with specific antibody. These results suggest that estrogen induces granulin gene expression in the hippocampus and that the product of this gene is involved in the mitogenic effects of estrogen in the dentate gyrus, although the responses to estrogen decline with age. Key words: Aging, Estrogen, Granulin, Hippocampus, Neurogenesis, Rat (J. Reprod. Dev. 53: [297][298][299][300][301][302][303][304][305][306][307] 2007) he brain has long been considered to be an organ that is not capable of regeneration. However, recent studies have shown the presence of active neurogenesis even in the brains of adult mammals [1]. Adult neurogenesis in the brain takes place principally in two distinct regions: the subventricular zone (SVZ) and the dentate gyrus of the hippocampus [2]. In the hippocampus, neural precursor cells are located in the subgranular zone (SGZ), which is the border region between the granule cell layer and the hilus in the dentate gyrus, and these precursor cells proliferate and produce daughter cells that are capable of differentiation into mature granule neurons [3]. Recent studies suggest that adult neurogenesis in the dentate gyrus is involved with learning [4,5] Among the factors regulating neurogenesis, more attention has been paid to estrogen since it is known to enhance cell proliferation and increase the number of immature neurons in the adult dentate gyrus [13][14][15]. In addition, a recent study indicated the presence of estrogen receptors (ERs) in neural stem cells in the SVZ and SGZ [16]. Estrogen also affects learning tasks [17,18] and the

Age-Dependent Changes in Progranulin Expression in the Mouse Brain

“…Further studies using neural and glial markers would be needed to examine the reason for this discrepancy. PGRN expressed in the hippocampus, especially in the dentate gyrus, is proposed to play roles in facilitating the estrogen-induced adult neurogenesis that takes place in this brain region [10]. The amygdala participates in inducing emotional reactions [19], and the PGRN-deficient mice showed an enhanced level of aggression and anxiety in our previous study [11].…”

“…Since the PGRN gene is a sex steroid-inducible gene, this age-dependent decrease in PGRN gene expression may be at least partially due to a decrease in the sex steroid levels in the peripheral circulation with age. On the other hand, we have previously shown that estrogen increases PGRN gene expression as well as neurogenesis in the hippocampus of 3-month-old rats, but the effects of estrogen on both gene expression and neurogenesis are no longer discernible in 12-month-old rats [10]. It is therefore suggested that the responsiveness to sex steroids in PGRN gene expression also declines with age.…”

“…In addition, we also suggested that PGRN plays a role in mediating the mitogenic effects of estrogen in the hippocampus of adult rats [10]. Subsequently, we generated a line of mice lacking the PGRN gene and found that PGRN-deficient mice exhibited enhanced anxiety and decreased male sexual behavior, suggesting that PGRN is indeed involved in masculinization of the rodent brain [11].…”

Perplexing Pax: From puzzle to paradigm

“…New neurons are produced from these progenitors in response to the mitogenic signals of EGF, TGF, VEGF and NPY (Craig et al, 1996;Kuhn et al, 1997;Tropepe et al, 1997;Schanzer et al, 2004;Howell et al, 2005;Chiba et al, 2007). The majority of these progenitor cells typically express Pax6 during proliferation with expression down-regulated upon exit from the cell cycle and entry into a migratory phase (Kohwi et al, 2005;Maekawa et al, 2005).…”

Alteration in Anxiety with Relation to the Volume of the Locus Ceruleus in Progranulin-Deficient Mice

“…Our previous studies have demonstrated that it mediates the organizing effects of sexsteroid hormones in the process of sexual differentiation of the brain [9][10][11][12][13]. PGRN also mediates estrogen-induced adult neurogenesis [14]. Mutations including the null mutation in the PGRN gene have been found in patients with frontotemporal dementia with ubiquitin-immunoreactive neuronal inclusions [15,16].…”