{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T05:20:42Z","timestamp":1788499242694,"version":"build-2803163510"},"reference-count":127,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Sex differences in the developing human brain are primarily attributed to hormonal influence. Recently however, genetic differences and their impact on the developing nervous system have attracted increased attention. To understand genetically driven sexual dimorphisms in neurodevelopment, we investigated genome-wide gene expression in an <jats:italic>in vitro<\/jats:italic> differentiation model of male and female human embryonic stem cell lines (hESC), independent of the effects of human sex hormones. Four male and four female-derived hESC lines were differentiated into a population of mixed neurons over 37\u00a0days. Differential gene expression and gene set enrichment analyses were conducted on bulk RNA sequencing data. While similar differentiation tendencies in all cell lines demonstrated the robustness and reproducibility of our differentiation protocol, we found sex-biased gene expression already in undifferentiated ESCs at day 0, but most profoundly after 37\u00a0days of differentiation. Male and female cell lines exhibited sex-biased expression of genes involved in neurodevelopment, suggesting that sex influences the differentiation trajectory. Interestingly, the highest contribution to sex differences was found to arise from the male transcriptome, involving both Y chromosome and autosomal genes. We propose 13 sex-biased candidate genes (10 upregulated in male cell lines and 3 in female lines) that are likely to affect neuronal development. Additionally, we confirmed gene dosage compensation of X\/Y homologs escaping X chromosome inactivation through their Y homologs and identified a significant overexpression of the Y-linked demethylase <jats:italic>UTY<\/jats:italic> and <jats:italic>KDM5D<\/jats:italic> in male hESC during neuron development, confirming previous results in neural stem cells. Our results suggest that genetic sex differences affect neuronal differentiation trajectories, which could ultimately contribute to sex biases during human brain development.<\/jats:p>","DOI":"10.3389\/fcell.2024.1341373","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T04:40:39Z","timestamp":1714538439000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Sex-biased gene expression during neural differentiation of human embryonic stem cells"],"prefix":"10.3389","volume":"12","author":[{"given":"Philipp","family":"Pottmeier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danai","family":"Nikolantonaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrik","family":"Lanner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Peuckert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Jazin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1159\/000509471","article-title":"Natural selection at the NHLH2 core promoter exceptionally long CA-repeat in human and disease-only genotypes in late-onset neurocognitive disorder","volume":"66","author":"Afshar","year":"2020","journal-title":"Gerontology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2548","DOI":"10.1016\/j.stemcr.2021.08.006","article-title":"Defining the nature of human pluripotent stem cell-derived interneurons via single-cell analysis","volume":"16","author":"Allison","year":"2021","journal-title":"Stem Cell Rep."},{"key":"B3","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1002\/jnr.23884","article-title":"A general theory of sexual differentiation","volume":"95","author":"Arnold","year":"2017","journal-title":"J. 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