Androgen Receptor signaling promotes the neural progenitor cell pool in the developing cortex. Issue 4 (7th October 2020)

• Record Type: Journal Article
• Authors: La Rosa, Piergiorgio; Bartoli, Giulia; Farioli Vecchioli, Stefano; Cesari, Eleonora; Pagliarini, Vittoria; Sette, Claudio
• Is Part Of: Journal of neurochemistry. Volume 157:Issue 4(2021)
• Page Start: 1153
• Page End: 1166
• Publication Date: 2020-10-07
• Subjects: Aldehyde Dehydrogenase 1 Family Member A3 -- androgen receptor -- cerebral cortex -- dihydrotestosterone -- neural progenitor cells; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15192
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: 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. Abstract : A surge in androgens occurs in a precise time window in male mouse embryo to ensure testis development. Administration of DHT, an active metabolite of testosterone, in neural progenitor cells (NPCs) activates the androgen receptor (AR), leading to the expression of the Aldehyde Dehydrogenase 1 Family Member A3 enzyme (ALDH1A3). In turn, ALDH1A3 activity contributes to maintain the NPC pool, thus increasing the number of neurons generated in the male cortex during cortical development. Such effect can be specifically suppressed by the AR inhibitor Enzalutamide. Thus, androgens can influence the balance between self‐renewal and neuronal differentiation, hence affecting neurogenesis in the developing mouse cortex.