The hypothalamus is one of the most complex brain regions in the central nervous system, and its neurons are highly diverse and control mammalian body homeostasis by regulating autonomic nerve, endocrine and instinctive behaviors. The hypothalamus not only ensures individual survival by regulating individual feeding, drinking water, body temperature, sleep, osmotic pressure, and circadian rhythm, but also controls puberty initiation and sexual reproductive capacity to ensure population reproduction. Although we have a deep insight into how the hypothalamus regulates feeding, sleep and body temperature, the mechanism involved in regulating puberty initiation remains unknown, which is listed as one of the 125 most cutting-edge scientific challenges by the Science.
Wu Qingfeng's team from the Institute of Genetic and Developmental Biology, Chinese Academy of Sciences, and his team from the School of Life Sciences, Tsinghua University, published a research paper titled: Hierarchical deployment of Tbx3 dictates the identity of hypothalamic KNDy neurons to control puberty onset online in the journal Science Advances.
While revealing the mechanism of mammalian puberty initiation from the perspective of developmental programming, this study also proposed a new paradigm that transcription factors regulating neuronal lineage ogenesis, which has important reference significance for subsequent theoretical studies.
Past genetic studies have shown that mutations in the transcription factor TBX3 can cause Ulnar-mammary syndrome (UMS), characterized by breast development defects and abnormal hand and forearm bone development, but the most noteworthy is the severe delayed onset of puberty in UMS patients.
In the work of Wu Qingfeng's team, the researchers found that Tbx3 defines a sublineage of the hypothalamus, and positively regulates the process of neuronal fate establishment and maintenance as a fate-determination subsequence.
At the animal level, Tbx3 gene defects have significantly delayed puberty, disrupted female hair cycles, ovarian ovulation and infertility, and Tbx3 plays an important role in establishing and maintaining the fate of hypothalamic KNDy neurons (key neurons that regulate puberty initiation). At the molecular level, the two teams found that Tbx3 regulates gene transcription through phase separation to induce neuropeptide expression. Notably, none of the multiple TBX3 mutants that cause UMS in humans failed to undergo efficient phase separation, and they also significantly lost the ability to regulate neuropeptide expression, leaving patients with symptoms of delayed initiation of puberty.
In the theoretical studies of hypothalamic lineage establishment and neurogenesis, By comparing two single-cell transcriptome databases, lineage tracing-based and gene-based manipulation, The finding that fate determinants can not only occur in a classical lineage-dependent manner, Neuronal fate can also be regulated in two lineage-independent ways, They were individually named intralineage retention (intra-lineage retention, ILR) and interlineage interaction (inter-lineage interaction, ILI), Both approaches may also be accompanied by lineage-independent compensation (lineage-independent compensation, LIC), Together, they determine the fate of the neurons in the brain during disease development.
Figure: Study overview.a. Lineage-dependent and lineage-independent fate determination mechanisms (ILR, intra-lineage retention; LIC, lineage-independent compensation; ILI, inter-lineage interaction), b. Key advances made at the molecular, cellular, and animal levels (TF, transcription factor; UMS, ulna breast syndrome)
Reviereviewers agreed during the review process that the study was "very interesting, in-depth, incorporating new data resources and scientific concepts, completed with very high quality and standards, and is likely to have important implications for the field of hypothalamic development".
In conclusion, this study took human genetic research as the entry point to reveal the process that Tbx3 sequence regulates the fate of the hypothalamic KNDy neurons and then induce puberty initiation, providing a new perspective on the developmental programming mechanisms of puberty initiation. Hypothalamic fate modulators are important regulatory elements that determine the development of neuronal fate, and the complex multiple regulatory network behind them is still worth exploring.
