Androgen Receptor signaling promotes the neural progenitor cell pool in the developing cortex

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.

Use of Brain-Derived Stem/Progenitor Cells and Derived Extracellular Vesicles to Repair Damaged Neural Tissues: Lessons Learned from Connective Tissue Repair Regarding Variables Limiting Progress and Approaches to Overcome Limitations

“…Differences between the sexes in tissue repair have been reported (reviewed in [ 53 ]) and sex-specific aspects of stem cells may contribute to such differences [ 54 , 55 ]. This concept is further supported by findings that estrogen can influence stem cell behavior [ 56 ] and androgens can influence neural progenitors [ 57 , 58 ]. Thus, the use of both NSC and MSC exhibit potential sex differences and their effectiveness could likely be influenced by the stage of life they are isolated from and the in vivo environment they are transplanted into to initiate repair.…”

Deciphering the role of precursor miR-12136 and miR-8485 in the progression of intellectual disability (ID)

“…The involvement of the target genes of these two miRNAs has been seen in various important biological processes like negative regulation of cell differentiation, prolactin signaling pathway, gland development ( Martínez-Alarcón et al, 2022 , Torner, 2016 Mar 30 ), and androgen receptor signaling pathway ( Lombardo et al, 2020 , La Rosa et al, 2021 ) which play an important role in the development and progression of neurodevelopmental disorders.…”

Sexually dimorphic phenotypes and the role of androgen receptors in UBE3A-dependent autism spectrum disorder

“…Following binding with androgens, the activated ARs will translocate into the nucleus to regulate gene expression. In addition to mediating sex hormone signaling and participating in important brain functions 37,39,40,46,48 , AR and many AR-regulated genes are known to be associated with ASD 5,[49][50][51][52][53][54][55][56][57][58][59][60][61] . Indeed, AR itself and at least seven ARGs are listed in the SFARI ASD gene database 5 .…”