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Moreover, the effect of 17-\u03b2-estradiol (E2) on axonal growth and Ngn3 expression is only found in male-derived neurons. To investigate whether sex chromosomes regulate these early sex differences in neuritogenesis by regulating the E2 effect on Ngn3, we evaluated the growth and differentiation of hypothalamic neurons derived from the \u201cfour core genotypes\u201d mouse model, in which the factors of \u201cgonadal sex\u201d and \u201csex chromosome complement\u201d are dissociated. We showed that sex differences in neurite outgrowth are determined by sex chromosome complement (XX\u2009&gt;\u2009XY). Moreover, E2 increased the mRNA expression of Ngn3 and axonal length only in XY neurons. ER\u03b1\/\u03b2 expressions are regulated by sex chromosome complement; however, E2-effect on Ngn3 expression in XY neurons was only fully reproduced by PPT, a specific ligand of ER\u03b1, and prevented by MPP, a specific antagonist of ER\u03b1. Together our data indicate that sex chromosomes regulate early development of hypothalamic neurons by orchestrating not only sex differences in neuritogenesis, but also regulating the effect of E2 on Ngn3 expression through activation of ER\u03b1 in hypothalamic neurons.<\/jats:p>","DOI":"10.1038\/s41598-020-65183-x","type":"journal-article","created":{"date-parts":[[2020,5,19]],"date-time":"2020-05-19T10:04:11Z","timestamp":1589882651000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Estradiol-dependent axogenesis and Ngn3 expression are determined by XY sex chromosome complement in hypothalamic neurons"],"prefix":"10.1038","volume":"10","author":[{"given":"Carla Daniela","family":"Cisternas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas Ezequiel","family":"Cabrera Zapata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco Rafael","family":"Mir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Julia","family":"Scerbo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Angeles","family":"Arevalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis Miguel","family":"Garcia-Segura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Julia","family":"Cambiasso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,19]]},"reference":[{"key":"65183_CR1","doi-asserted-by":"publisher","first-page":"2096","DOI":"10.1111\/j.1460-9568.2010.07511.x","volume":"32","author":"KM Lenz","year":"2010","unstructured":"Lenz, K. 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