Journal
JOURNAL OF NEUROCHEMISTRY
Volume 157, Issue 4, Pages 1153-1166Publisher
WILEY
DOI: 10.1111/jnc.15192
Keywords
Aldehyde Dehydrogenase 1 Family Member A3; androgen receptor; cerebral cortex; dihydrotestosterone; neural progenitor cells
Categories
Funding
- Italian Ministry of Health [GR-2018-12365706]
- Associazione Italiana Ricerca sul Cancro [IG23416]
- Italian Ministry of University and Research [PRIN 2017 2017P352Z4]
- Ministry of Health
- Fondazione Umberto Veronesi
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This study investigated the role of dihydrotestosterone (DHT) in regulating neural progenitor cell (NPC) stemness and differentiation, revealing that DHT activates androgen receptor (AR) to increase NPC proliferation and reduce neuronal differentiation. The findings suggest that androgens engage an AR-dependent signaling pathway to impact neurogenesis by expanding the NPC pool in the developing mouse cortex.
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.
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