{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T17:37:47Z","timestamp":1793381867942,"version":"4.5.0"},"reference-count":97,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T00:00:00Z","timestamp":1664841600000},"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>\n                    Kdm6a is an X-chromosome-linked H3K27me2\/3 demethylase that promotes chromatin accessibility and gene transcription and is critical for tissue\/cell-specific differentiation. Previous results showed higher\n                    <jats:italic>Kdm6a<\/jats:italic>\n                    levels in XX than in XY hypothalamic neurons and a female-specific requirement for Kdm6a in mediating increased axogenesis before brain masculinization. Here, we explored the sex-specific role of Kdm6a in the specification of neuronal subtypes in the developing hypothalamus. Hypothalamic neuronal cultures were established from sex-segregated E14 mouse embryos and transfected with siRNAs to knockdown Kdm6a expression (Kdm6a-KD). We evaluated the effect of Kdm6a-KD on Ngn3 expression, a bHLH transcription factor regulating neuronal sub-specification in hypothalamus. Kdm6a-KD decreased Ngn3 expression in females but not in males, abolishing basal sex differences. Then, we analyzed Kdm6a-KD effect on\n                    <jats:italic>Ascl1<\/jats:italic>\n                    ,\n                    <jats:italic>Pomc<\/jats:italic>\n                    ,\n                    <jats:italic>Npy<\/jats:italic>\n                    ,\n                    <jats:italic>Sf1<\/jats:italic>\n                    ,\n                    <jats:italic>Gad1<\/jats:italic>\n                    , and\n                    <jats:italic>Th<\/jats:italic>\n                    expression by RT-qPCR. While Kdm6a-KD downregulated\n                    <jats:italic>Ascl1<\/jats:italic>\n                    in both sexes equally, we found sex-specific effects for\n                    <jats:italic>Pomc<\/jats:italic>\n                    ,\n                    <jats:italic>Npy<\/jats:italic>\n                    , and\n                    <jats:italic>Th<\/jats:italic>\n                    .\n                    <jats:italic>Pomc<\/jats:italic>\n                    and\n                    <jats:italic>Th<\/jats:italic>\n                    expressed higher in female than in male neurons, and Kdm6a-KD reduced their levels only in females, while\n                    <jats:italic>Npy<\/jats:italic>\n                    expressed higher in male than in female neurons, and Kdm6a-KD upregulated its expression only in females. Identical results were found by immunofluorescence for Pomc and Npy neuropeptides. Finally, using ChIP-qPCR, we found higher H3K27me3 levels at\n                    <jats:italic>Ngn3<\/jats:italic>\n                    ,\n                    <jats:italic>Pomc<\/jats:italic>\n                    , and\n                    <jats:italic>Npy<\/jats:italic>\n                    promoters in male neurons, in line with Kdm6a higher expression and demethylase activity in females. At all three promoters, Kdm6a-KD induced an enrichment of H3K27me3 only in females. These results indicate that Kdm6a plays a sex-specific role in controlling the expression of transcription factors and neuropeptides critical for the differentiation of hypothalamic neuronal populations regulating food intake and energy homeostasis.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2022.937875","type":"journal-article","created":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T02:51:02Z","timestamp":1664851862000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Epigenetic modifier Kdm6a\/Utx controls the specification of hypothalamic neuronal subtypes in a sex-dependent manner"],"prefix":"10.3389","volume":"10","author":[{"given":"Lucas E.","family":"Cabrera Zapata","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Julia","family":"Cambiasso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Angeles","family":"Arevalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s00441-018-2859-1","article-title":"Development of neuroendocrine neurons in the mammalian hypothalamus","volume":"375","author":"Alvarez-Bolado","year":"2019","journal-title":"Cell Tissue Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1242\/dmm.011916","article-title":"Conditional deletion of neurogenin-3 using Nkx2.1iCre results in a mouse model for the central control of feeding, activity and obesity","volume":"6","author":"Anthwal","year":"2013","journal-title":"Dis. 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