Androgens Increase Excitatory Neurogenic Potential in Human Brain Organoids

Overview

Journal Nature

Specialty Science

Date 2022 Jan 20

PMID 35046577

Authors

Iva Kelava

Ilaria Chiaradia

Laura Pellegrini

Alex T Kalinka

Madeline A Lancaster

Affiliations

Soon will be listed here.

Abstract

The biological basis of male-female brain differences has been difficult to elucidate in humans. The most notable morphological difference is size, with male individuals having on average a larger brain than female individuals, but a mechanistic understanding of how this difference arises remains unknown. Here we use brain organoids to show that although sex chromosomal complement has no observable effect on neurogenesis, sex steroids-namely androgens-lead to increased proliferation of cortical progenitors and an increased neurogenic pool. Transcriptomic analysis and functional studies demonstrate downstream effects on histone deacetylase activity and the mTOR pathway. Finally, we show that androgens specifically increase the neurogenic output of excitatory neuronal progenitors, whereas inhibitory neuronal progenitors are not increased. These findings reveal a role for androgens in regulating the number of excitatory neurons and represent a step towards understanding the origin of sex-related brain differences in humans.

Citing Articles

Regulating Integrin β1 to Restore Gonadotropin-Releasing Hormone-Tanycyte Unit Function in Polycystic Ovary Syndrome-Related Hypothalamic Dysregulation.

Wang Y, Tong X, Xiao Y, Wang Y, Hu W, Lu W Research (Wash D C). 2025; 8:0619.

PMID: 39975575 PMC: 11836200. DOI: 10.34133/research.0619.

Chronic exposure to glucocorticoids amplifies inhibitory neuron cell fate during human neurodevelopment in organoids.

Dony L, Krontira A, Kaspar L, Ahmad R, Demirel I, Grochowicz M Sci Adv. 2025; 11(7):eadn8631.

PMID: 39951527 PMC: 11827642. DOI: 10.1126/sciadv.adn8631.

Dysregulation of mTOR signalling is a converging mechanism in lissencephaly.

Zhang C, Liang D, Ercan-Sencicek A, Bulut A, Cortes J, Cheng I Nature. 2025; 638(8049):172-181.

PMID: 39743596 PMC: 11798849. DOI: 10.1038/s41586-024-08341-9.

Embracing sex-specific differences in engineered kidney models for enhanced biological understanding of kidney function.

Veser C, Carlier A, Dubois V, Mihaila S, Swapnasrita S Biol Sex Differ. 2024; 15(1):99.

PMID: 39623463 PMC: 11613810. DOI: 10.1186/s13293-024-00662-8.

Inferring disease progression stages in single-cell transcriptomics using a weakly supervised deep learning approach.

Wehbe F, Adams L, Babadoudou J, Yuen S, Kim Y, Tanaka Y Genome Res. 2024; 35(1):135-146.

PMID: 39622637 PMC: 11789631. DOI: 10.1101/gr.278812.123.

References

Kim W . Brain size is controlled by the mammalian target of rapamycin (mTOR) in mice. Commun Integr Biol. 2016; 8(1):e994377. PMC: 4594332. DOI: 10.4161/19420889.2014.994377. View

Abrahams B, Arking D, Campbell D, Mefford H, Morrow E, Weiss L . SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs). Mol Autism. 2013; 4(1):36. PMC: 3851189. DOI: 10.1186/2040-2392-4-36. View

Fatemi S, Folsom T, Thuras P . Deficits in GABA(B) receptor system in schizophrenia and mood disorders: a postmortem study. Schizophr Res. 2011; 128(1-3):37-43. PMC: 3085603. DOI: 10.1016/j.schres.2010.12.025. View

Hines M, Constantinescu M, Spencer D . Early androgen exposure and human gender development. Biol Sex Differ. 2015; 6:3. PMC: 4350266. DOI: 10.1186/s13293-015-0022-1. View

Tang T, Zhang Y, Wang Y, Cai Z, Lu Z, Li L . HDAC1 and HDAC2 Regulate Intermediate Progenitor Positioning to Safeguard Neocortical Development. Neuron. 2019; 101(6):1117-1133.e5. DOI: 10.1016/j.neuron.2019.01.007. View

Bahari-Javan S, Varbanov H, Halder R, Benito E, Kaurani L, Burkhardt S . HDAC1 links early life stress to schizophrenia-like phenotypes. Proc Natl Acad Sci U S A. 2017; 114(23):E4686-E4694. PMC: 5468618. DOI: 10.1073/pnas.1613842114. View

Leek J, Johnson W, Parker H, Jaffe A, Storey J . The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012; 28(6):882-3. PMC: 3307112. DOI: 10.1093/bioinformatics/bts034. View

Davey R, Grossmann M . Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin Biochem Rev. 2016; 37(1):3-15. PMC: 4810760. View

Martinez-Cerdeno V, Noctor S, Kriegstein A . Estradiol stimulates progenitor cell division in the ventricular and subventricular zones of the embryonic neocortex. Eur J Neurosci. 2007; 24(12):3475-88. DOI: 10.1111/j.1460-9568.2006.05239.x. View

10.

Friedman J, Hastie T, Tibshirani R . Regularization Paths for Generalized Linear Models via Coordinate Descent. J Stat Softw. 2010; 33(1):1-22. PMC: 2929880. View

11.

Eliot L, Ahmed A, Khan H, Patel J . Dump the "dimorphism": Comprehensive synthesis of human brain studies reveals few male-female differences beyond size. Neurosci Biobehav Rev. 2021; 125:667-697. DOI: 10.1016/j.neubiorev.2021.02.026. View

12.

Quartier A, Chatrousse L, Redin C, Keime C, Haumesser N, Maglott-Roth A . Genes and Pathways Regulated by Androgens in Human Neural Cells, Potential Candidates for the Male Excess in Autism Spectrum Disorder. Biol Psychiatry. 2018; 84(4):239-252. DOI: 10.1016/j.biopsych.2018.01.002. View

13.

Abel K, Drake R, Goldstein J . Sex differences in schizophrenia. Int Rev Psychiatry. 2010; 22(5):417-28. DOI: 10.3109/09540261.2010.515205. View

14.

McCarthy M . Multifaceted origins of sex differences in the brain. Philos Trans R Soc Lond B Biol Sci. 2016; 371(1688):20150106. PMC: 4785894. DOI: 10.1098/rstb.2015.0106. View

15.

Qu Y, Dai B, Ye D, Kong Y, Chang K, Jia Z . Constitutively active AR-V7 plays an essential role in the development and progression of castration-resistant prostate cancer. Sci Rep. 2015; 5:7654. PMC: 4288210. DOI: 10.1038/srep07654. View

16.

Bagley J, Reumann D, Bian S, Levi-Strauss J, Knoblich J . Fused cerebral organoids model interactions between brain regions. Nat Methods. 2017; 14(7):743-751. PMC: 5540177. DOI: 10.1038/nmeth.4304. View

17.

Sohal V, Rubenstein J . Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders. Mol Psychiatry. 2019; 24(9):1248-1257. PMC: 6742424. DOI: 10.1038/s41380-019-0426-0. View

18.

Dey A, Robitaille M, Remke M, Maier C, Malhotra A, Gregorieff A . YB-1 is elevated in medulloblastoma and drives proliferation in Sonic hedgehog-dependent cerebellar granule neuron progenitor cells and medulloblastoma cells. Oncogene. 2016; 35(32):4256-68. PMC: 4931992. DOI: 10.1038/onc.2015.491. View

19.

Green T, Flash S, Reiss A . Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies. Neuropsychopharmacology. 2018; 44(1):9-21. PMC: 6235860. DOI: 10.1038/s41386-018-0153-2. View

20.

Alexeyenko A, Schmitt T, Tjarnberg A, Guala D, Frings O, Sonnhammer E . Comparative interactomics with Funcoup 2.0. Nucleic Acids Res. 2011; 40(Database issue):D821-8. PMC: 3245127. DOI: 10.1093/nar/gkr1062. View