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As human genetic studies have recently established a link between TBX3 mutations and delayed puberty onset, we systematically studied Tbx3-derived neuronal lineage and Tbx3-dependent neuronal specification and found that Tbx3 hierarchically established and maintained the identity of KNDy neurons for triggering puberty. Apart from the well-established lineage-dependent fate determination, we uncovered rules of interlineage interaction and intralineage retention operating through neuronal differentiation in the absence of Tbx3. Moreover, we revealed that human TBX3 mutations disturbed the phase separation of encoded proteins and impaired transcriptional regulation of key neuropeptides, providing a pathological mechanism underlying TBX3-associated puberty disorders.<\/jats:p>","DOI":"10.1126\/sciadv.abq2987","type":"journal-article","created":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T18:58:34Z","timestamp":1668625114000},"source":"Crossref","is-referenced-by-count":15,"title":["Hierarchical deployment of Tbx3 dictates the identity of hypothalamic KNDy neurons to control puberty onset"],"prefix":"10.1126","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2823-3741","authenticated-orcid":true,"given":"Xiang","family":"Shi","sequence":"first","affiliation":[{"name":"State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China."},{"name":"University of Chinese Academy of Sciences, Beijing 100101, 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