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Cited by 17Hypothalamic control of reproductive hormonesDevelopmental Biology and Gene RegulationNeurogenesis and neuroplasticity mechanisms

Hierarchical deployment of Tbx3 dictates the identity of hypothalamic KNDy neurons to control puberty onset

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Shi, Xiang, Zhuang, Yanrong, Chen, Zhenhua, Xu, Mingrui, Kuang, Junqi, Sun, Xue-Lian, Gao, Lisen, Kuang, Xia +9 more·2022·Science Advances
DOI 10.1126/sciadv.abq2987PMC PMC9668310
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Abstract

The neuroendocrine system consists of a heterogeneous collection of neuropeptidergic neurons in the brain, among which hypothalamic KNDy neurons represent an indispensable cell subtype controlling puberty onset. Although neural progenitors and neuronal precursors along the cell lineage hierarchy adopt a cascade diversification strategy to generate hypothalamic neuronal heterogeneity, the cellular logic operating within the lineage to specify a subtype of neuroendocrine neurons remains unclear. 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.

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  • TBX3 has been shown to directly promote the expression of target genes by binding to specific DNA sequences within those genes.

    “TBX3 has been shown to directly promote the expression of target genes by binding to specific DNA sequences within those genes.”

    From TBX3 shapes an immunosuppressive microenvironment and induces immunotherapy resistance (2025) · cites this paper as [77]

  • Xiang Shi et al. found an enrichment of the GTGT motif in the promoters of human TAC3 and KISS1 genes and a robust stimulatory action of hTBX3 on these promoters, which promotes the expression of TAC3 and KISS1.

    “Xiang Shi et al. found an enrichment of the GTGT motif in the promoters of human TAC3 and KISS1 genes and a robust stimulatory action of hTBX3 on these promoters, which promotes the expression of TAC3 and KISS1 77.”

    From TBX3 shapes an immunosuppressive microenvironment and induces immunotherapy resistance (2025) · cites this paper as [77]

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Authors
Shi, X., Zhuang, Y., Chen, Z., Xu, M., Kuang, J., Sun, X.-L., Gao, L., Kuang, X., Zhang, H., Li, W., Wong, S. Z. H., Liu, C., Liu, L., Jiang, D., Pei, D., Lin, Y., & Wu, Q.-F.
Affiliations
  • Chinese Academy of Sciences (CN)
  • Center for Life Sciences (CN)
  • State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
  • Stanford Medicine (US)
  • BGI Group (China) (CN)
  • Westlake University (CN)
Corresponding author
  • Shi, Xiang
  • Zhuang, Yanrong
  • Chen, Zhenhua
  • Lin, Yi
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-11-16
Volume
8
Issue
46
Pages
eabq2987-eabq2987
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.abq2987
PMC
PMC9668310
OpenAlex
W4309323494
Cited by
17
References
62
Citations by year
2026: 3 · 2025: 11 · 2024: 1 · 2023: 2
FWCI
2.95
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
TBX3, KNDy neurons, hypothalamus, puberty onset, neuroendocrine neurons, neuronal specification, delayed puberty, phase separation
MeSH terms
Animals, Humans, Hypothalamus, Neurons, Neuropeptides, Puberty, Cell Lineage, T-Box Domain Proteins, Mice

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