TY - JOUR
T1 - Androgen Receptor signaling promotes the neural progenitor cell pool in the developing cortex
AU - La Rosa, Piergiorgio
AU - Bartoli, Giulia
AU - Farioli Vecchioli, Stefano
AU - Cesari, Eleonora
AU - Pagliarini, Vittoria
AU - Sette, Claudio
N1 - Funding Information:
We thank Dr. Elisabetta Volpe for the assistance with the flow cytometric analyses. This work was supported by grants from Italian Ministry of University and Research (MIUR) [PRIN 2017 2017P352Z4 to C.S.]; Associazione Italiana Ricerca sul Cancro (AIRC) [Grant IG23416 to C.S.]; and Italian Ministry of Health [GR‐2018‐12365706 to V.P.]. PGL was partly supported by a scholarship from Fondazione Umberto Veronesi.
Publisher Copyright:
© 2020 International Society for Neurochemistry
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/9
Y1 - 2020/9
N2 - Neural Progenitor Cells (NPCs) are multipotent cells that are able to self-renew and differentiate into neurons. The size of the initial pool of NPCs during the brain development strongly affects the number of neurons that compose cortical multi-layer during development. Gonadal hormones can influence the balance between self-renewal and differentiation processes. Herein, we investigated the role of dihydrotestosterone (DHT), the active metabolite of testosterone, in the regulation of NPC stemness and differentiation. First, we evaluated the expression of the androgen receptor (AR), the transcription factor activated by DHT that mediates the physiological effects of androgens, in NPCs. Western blot analysis showed that DHT-mediated activation of AR induces mitogenic signaling pathways (PI3K/AKT and MAPK/ERK) in NPCs, whereas luciferase activity assays demonstrated the induction of AR transcriptional activity. AR activation mediated by DHT treatment strongly increased the proliferation of NPCs and reduced their propensity to differentiate into neurons. Furthermore, the effects of AR activation were mediated, at least in part, by increased expression of Aldehyde Dehydrogenase 1 Family Member A3 enzyme (ALDH1A3). Pharmacological inhibition of ALDH activity with N,N-diethylaminobenzaldehyde (DEAB) reduced the effect of DHT on NPC proliferation in vitro. Furthermore, inhibition of AR activity by Enzalutamide reduced the NPC pool in the developing cortex of male C57/BL6 mouse embryos. These findings indicate that androgens engage an AR-dependent signaling pathway that impact on neurogenesis by increasing the NPC pool in the developing mouse cortex. (Figure presented.).
AB - Neural Progenitor Cells (NPCs) are multipotent cells that are able to self-renew and differentiate into neurons. The size of the initial pool of NPCs during the brain development strongly affects the number of neurons that compose cortical multi-layer during development. Gonadal hormones can influence the balance between self-renewal and differentiation processes. Herein, we investigated the role of dihydrotestosterone (DHT), the active metabolite of testosterone, in the regulation of NPC stemness and differentiation. First, we evaluated the expression of the androgen receptor (AR), the transcription factor activated by DHT that mediates the physiological effects of androgens, in NPCs. Western blot analysis showed that DHT-mediated activation of AR induces mitogenic signaling pathways (PI3K/AKT and MAPK/ERK) in NPCs, whereas luciferase activity assays demonstrated the induction of AR transcriptional activity. AR activation mediated by DHT treatment strongly increased the proliferation of NPCs and reduced their propensity to differentiate into neurons. Furthermore, the effects of AR activation were mediated, at least in part, by increased expression of Aldehyde Dehydrogenase 1 Family Member A3 enzyme (ALDH1A3). Pharmacological inhibition of ALDH activity with N,N-diethylaminobenzaldehyde (DEAB) reduced the effect of DHT on NPC proliferation in vitro. Furthermore, inhibition of AR activity by Enzalutamide reduced the NPC pool in the developing cortex of male C57/BL6 mouse embryos. These findings indicate that androgens engage an AR-dependent signaling pathway that impact on neurogenesis by increasing the NPC pool in the developing mouse cortex. (Figure presented.).
KW - Aldehyde Dehydrogenase 1 Family Member A3
KW - androgen receptor
KW - cerebral cortex
KW - dihydrotestosterone
KW - neural progenitor cells
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U2 - 10.1111/jnc.15192
DO - 10.1111/jnc.15192
M3 - Article
C2 - 32959393
AN - SCOPUS:85092130767
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
ER -