Roles of Progranulin in Sexual Differentiation of the Developing Brain and Adult Neurogenesis

Suzuki, Masatoshi; Lee, Hwi-Cheul; Kayasuga, Yuko; Chiba, Shuichi; Nedachi, Taku; Matsuwaki, Takashi; Yamanouchi, Keitaro; Nishihara, Masugi

doi:10.1262/jrd.20249

Cited by 45 publications

(30 citation statements)

References 61 publications

(61 reference statements)

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“…We previously identified PGRN as one of the factors involved in masculinization of the rodent brain [6][7][8][9]. We have shown that both androgen [6] and estrogen [8] induced PGRN gene …”

Section: Discussionmentioning

confidence: 97%

“…The PGRN protein is processed into peptides of approximately 6 kDa called granulins [2,4], also known as epithelins [5]. Although both PGRN and granulins have growth-modulating effects on many types of cells in culture [4,5], little is known about their precise molecular mechanisms of action.We have identified PGRN as one of the genes that are upregulated in the hypothalamus by sex steroids during the perinatal period and are involved in sexual differentiation of the rat brain [6][7][8][9]. In addition, we also suggested that PGRN plays a role in mediating the mitogenic effects of estrogen in the hippocampus of adult rats [10].…”

mentioning

confidence: 80%

“…We have identified PGRN as one of the genes that are upregulated in the hypothalamus by sex steroids during the perinatal period and are involved in sexual differentiation of the rat brain [6][7][8][9]. In addition, we also suggested that PGRN plays a role in mediating the mitogenic effects of estrogen in the hippocampus of adult rats [10].…”

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confidence: 80%

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Age-Dependent Changes in Progranulin Expression in the Mouse Brain

Matsuwaki

Asakura

Suzuki

et al. 2011

Journal of Reproduction and Development

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Abstract. The progranulin (PGRN) gene is involved in sexual differentiation of the brain during the perinatal period and estrogen-induced adult neurogenesis in the hippocampus. Mutations in the PGRN gene are also implicated in human frontotemporal lobar degeneration. Thus, while PGRN appears to play important roles as a growth factor in the brain, the localization of PGRN-expressing cells throughout the brain has not been fully established. In the present study, we examined the localization of PGRN proteins in the brain using adult male wild-type mice and PGRNdeficient mice we had generated previously. We also evaluated age-dependent changes in PGRN expression at the mRNA and protein levels. As expected, no immunoreactivity was observed in the brains of the PGRN-deficient mice. In the wild-type mice, intense immunoreactivity was observed in several brain regions including the cingulate and piriform cortices, the pyramidal cell layer and dentate gyrus of the hippocampus, the amygdala, the ventromedial and arcuate nuclei of the hypothalamus and the Purkinje cell layer in the cerebellum. Moreover, PGRN mRNA and protein expression decreased in the cortex, hippocampus and hypothalamus in an age-dependent manner. Since many of these brain regions are involved in emotion, memory and recognition, PGRN may play roles as a growth factor in these brain functions that decline with age. Key words: Aging, Brain, Gene expression, Immunohistochemistry, Progranulin (J. Reprod. Dev. 57: [113][114][115][116][117][118][119] 2011) he progranulin (PGRN) gene spans approximately 6.3 kbp and encodes a 68.5-kDa protein containing 7.5 tandem granulin motif repeats [1]. PGRN mRNA is expressed in various tissues and organs, including the reproductive organs, gastrointestinal tract, endocrine organs and neural tissues [2,3]. The PGRN protein is processed into peptides of approximately 6 kDa called granulins [2,4], also known as epithelins [5]. Although both PGRN and granulins have growth-modulating effects on many types of cells in culture [4,5], little is known about their precise molecular mechanisms of action.We have identified PGRN as one of the genes that are upregulated in the hypothalamus by sex steroids during the perinatal period and are involved in sexual differentiation of the rat brain [6][7][8][9]. 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]. Recently, PGRN has been identified as one of the major factors causing frontotemporal lobar degeneration (FTLD) in humans. In studies on the frequency of mutations in the FTLD population, 5-10% of the patients were found to have mutations in the PGRN gene [12,13]. Taken together, these observations suggest that PGRN plays important roles in the brain ...

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“…We previously identified PGRN as one of the factors involved in masculinization of the rodent brain [6][7][8][9]. We have shown that both androgen [6] and estrogen [8] induced PGRN gene …”

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 80%

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Age-Dependent Changes in Progranulin Expression in the Mouse Brain

Matsuwaki

Asakura

Suzuki

et al. 2011

Journal of Reproduction and Development

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“…Our GRN methylation data also supports this finding, as males have reduced promoter methylation, suggesting a derepressed state primed for transcriptional activation. These data are intriguing considering that progranulin expression in rat hippocampus was found to be under the control of estrogen 43. Although there have been numerous studies describing sex dimorphisms in gene methylation in peripheral blood, these studies have failed to specifically identify progranulin 44, 45.…”

Section: Discussionmentioning

confidence: 99%

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

Cooper

Nachun

Dokuru

et al. 2018

Ann Clin Transl Neurol

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ObjectiveChanges in progranulin (GRN) expression have been hypothesized to alter risk for Alzheimer's disease (AD). We investigated the relationship between GRN expression in peripheral blood and clinical diagnosis of AD and mild cognitive impairment (MCI).MethodsPeripheral blood progranulin gene expression was measured, using microarrays from Alzheimer's (n = 186), MCI (n = 118), and control (n = 204) subjects from the University of California San Francisco Memory and Aging Center (UCSF‐MAC) and two independent published series (AddNeuroMed and ADNI). GRN gene expression was correlated with clinical, demographic, and genetic data, including APOE haplotype and the GRN rs5848 single‐nucleotide polymorphism. Finally, we assessed progranulin protein levels, using enzyme‐linked immunosorbent assay, and methylation status using methylation microarrays.ResultsWe observed an increase in blood progranulin gene expression and a decrease in GRN promoter methylation in males (P = 0.007). Progranulin expression was 13% higher in AD and MCI patients compared with controls in the UCSF‐MAC cohort (F 2,505 = 10.41, P = 3.72*10−5). This finding was replicated in the AddNeuroMed (F 2,271 = 17.9, P = 4.83*10−8) but not the ADNI series. The rs5848 SNP (T‐allele) predicted decreased blood progranulin gene expression (P = 0.03). The APOE4 haplotype was positively associated with progranulin expression independent of diagnosis (P = 0.04). Finally, we did not identify differences in plasma progranulin protein levels or gene methylation between diagnostic categories.InterpretationProgranulin mRNA is elevated in peripheral blood of patients with AD and MCI and its expression is associated with numerous genetic and demographic factors. These data suggest a role in the pathogenesis of neurodegenerative dementias besides frontotemporal dementia.

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“…We have identified PGRN as one of the factors involved in sexual differentiation of the rodent brain and adult neurogenesis in the hippocampus [2][3][4][5]. In addition, PGRN exerts neurotropic effects under several experimental conditions [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Possible involvement of the cerebellum in motor-function impairment in progranulin-deficient mice

et al. 2015

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Progranulin (PGRN) is a multifunctional growth factor involved in many physiological and pathological processes in the brain such as sexual differentiation, neurogenesis, neuroinflammation, and neurodegeneration. Previously, we showed that PGRN was expressed broadly in the brain and the Purkinje cells in the cerebellum were one of the regions with the highest expression level of PGRN. Thus, in the present study, we investigated the possible roles of PGRN in the cerebellum by comparing wild-type (WT) and PGRN-deficient (KO) mice with immunohistochemical staining for calbindin, a marker of Purkinje cells. The results showed that the density of Purkinje cell dendrites in the molecular layer of the cerebellum was significantly higher in KO mice than in WT mice, although the number of cell bodies was comparable between the genotypes. Subsequently, as the cerebellum is the center of the motor function, we performed a rotarod test and found that KO mice remained on the rotating rod for significantly shorter periods than WT mice. However, KO and WT mice did not differ significantly with respect to the diameter of myofibers in a skeletal muscle. These results suggest that PGRN is involved in the development and/or maturation of neuronal networks comprising Purkinje cells in the cerebellum, which may be a prerequisite to normal motor function.

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Roles of Progranulin in Sexual Differentiation of the Developing Brain and Adult Neurogenesis

Cited by 45 publications

References 61 publications

Age-Dependent Changes in Progranulin Expression in the Mouse Brain

Age-Dependent Changes in Progranulin Expression in the Mouse Brain

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

Possible involvement of the cerebellum in motor-function impairment in progranulin-deficient mice

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