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Mol. Life Sci."],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Several X-linked genes are involved in neuronal differentiation and may contribute to the generation of sex dimorphisms in the brain. Previous results showed that XX hypothalamic neurons grow faster, have longer axons, and exhibit higher expression of the neuritogenic gene\n                    <jats:italic>neurogenin 3<\/jats:italic>\n                    (\n                    <jats:italic>Ngn3<\/jats:italic>\n                    ) than XY before perinatal masculinization. Here we evaluated the participation of candidate X-linked genes in the development of these sex differences, focusing mainly on\n                    <jats:italic>Kdm6a<\/jats:italic>\n                    , a gene encoding for an H3K27 demethylase with functions controlling gene expression genome-wide. We established hypothalamic neuronal cultures from wild-type or transgenic Four Core Genotypes mice, a model that allows evaluating the effect of sex chromosomes independently of gonadal type. X-linked genes\n                    <jats:italic>Kdm6a<\/jats:italic>\n                    ,\n                    <jats:italic>Eif2s3x<\/jats:italic>\n                    and\n                    <jats:italic>Ddx3x<\/jats:italic>\n                    showed higher expression in XX compared to XY neurons, regardless of gonadal sex. Moreover,\n                    <jats:italic>Kdm6a<\/jats:italic>\n                    expression pattern with higher mRNA levels in XX than XY did not change with age at E14, P0, and P60 in hypothalamus or under 17\u03b2-estradiol treatment in culture. Kdm6a pharmacological blockade by GSK-J4 reduced axonal length only in female neurons and decreased the expression of neuritogenic genes\n                    <jats:italic>Neurod1<\/jats:italic>\n                    ,\n                    <jats:italic>Neurod2<\/jats:italic>\n                    and\n                    <jats:italic>Cdk5r1<\/jats:italic>\n                    in both sexes equally, while a sex-specific effect was observed in\n                    <jats:italic>Ngn3<\/jats:italic>\n                    . Finally,\n                    <jats:italic>Kdm6a<\/jats:italic>\n                    downregulation using siRNA reduced axonal length and\n                    <jats:italic>Ngn3<\/jats:italic>\n                    expression only in female neurons, abolishing the sex differences observed in control conditions. Altogether, these results point to\n                    <jats:italic>Kdm6a<\/jats:italic>\n                    as a key mediator of the higher axogenesis and\n                    <jats:italic>Ngn3<\/jats:italic>\n                    expression observed in XX neurons before the critical period of brain masculinization.\n                  <\/jats:p>","DOI":"10.1007\/s00018-021-03945-0","type":"journal-article","created":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T08:05:12Z","timestamp":1633939512000},"page":"7043-7060","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["X-linked histone H3K27 demethylase Kdm6a regulates sexually dimorphic differentiation of hypothalamic neurons"],"prefix":"10.1007","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3999-9985","authenticated-orcid":false,"given":"Lucas E.","family":"Cabrera Zapata","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6497-9479","authenticated-orcid":false,"given":"Carla D.","family":"Cisternas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4694-5371","authenticated-orcid":false,"given":"Camila","family":"Sosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2450-2916","authenticated-orcid":false,"given":"Luis Miguel","family":"Garcia-Segura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4303-9576","authenticated-orcid":false,"given":"Maria Angeles","family":"Arevalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3738-4699","authenticated-orcid":false,"given":"Mar\u00eda Julia","family":"Cambiasso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,11]]},"reference":[{"issue":"2","key":"3945_CR1","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.yfrne.2011.02.007","volume":"32","author":"AM Bao","year":"2011","unstructured":"Bao AM, Swaab DF (2011) Sexual differentiation of the human brain: relation to gender identity, sexual orientation and neuropsychiatric disorders. 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