The hypothalamus, one of the most complex brain regions in the mammalian nervous system, contains an amazing heterogeneity of neurons that regulate endocrine, autonomic, and behavioral functions. It not only regulates food intake, water intake, body temperature, circadian rhythms, and sleep to maintain the survival of individual organisms, but also controls puberty onset and reproductive behavior to maintain the breeding population.
“What Triggers Puberty” is one of the 125 Big Questions asked in the anniversary edition of 125 Science Magazine. Researchers led by Prof. WU Qingfeng from the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences have found that the developmental programming of the onset of puberty depends on TBX3. They also uncovered new rules for lineage progression that operate through neuronal differentiation during hypothalamic development.
The results were published in scientific advances on Nov 16
In this study, Prof. WU’s group found that TBX3 defines a progenitor domain in the developing hypothalamus and serves as a fate determinant to sequentially control the establishment and maintenance of neuronal fate.
The neuroendocrine system consists of a heterogeneous assembly of neuropeptidergic neurons in the brain, among which hypothalamic KNDy neurons represent an essential cell subtype that controls the onset of puberty. Although hypothalamic neural progenitors and neuronal progenitors along the lineage hierarchy have been proposed to employ a cascade diversification strategy to generate extreme neuronal diversity, the cellular logic for specifying a subtype of neuroendocrine neurons has been unclear.
Previous genetic studies suggest that genetic mutations in TBX3 cause Ulnar Mammary Syndrome (UMS), which is characterized by shortened forelimbs, defective mammary gland development, and genital abnormalities. It is noteworthy that most EMS patients have a delayed onset of puberty.
According to the researchers, at the level of the organism, there is a genetic ablation of tbx3 significantly delays the onset of puberty in animals and disrupts the oestrous cycle in female mice. At the cellular level, TBX3 plays an important role in establishing and maintaining the fate of KNDy neurons in the hypothalamus. Furthermore, at the molecular level, TBX3 regulates gene transcription via phase separation and thereby induces neuropeptide expression in hypothalamic neurons.
Important, multiple times TBX3 Mutants identified in EMS patients do not form phase-separated condensates and cannot efficiently regulate neuropeptide expression, a pathological mechanism underlying delayed puberty in EMS patients.
In addition, Prof. WU wanted to answer how neuronal lineage progresses during hypothalamic development under physiological and pathological conditions. He and his colleagues used an unprecedented cell-type targeting strategy by comparing single-cell datasets from lineage-tracing and genetically engineered mice, and uncovered two lineage-independent rules – the intra-lineage retention (ILR) and the inter-lineage interaction (ILI). regulate lineage progression under pathological conditions.
Overall, this study reveals the underlying cellular and molecular mechanisms TBX3 Mutations disrupt the onset of puberty in UMS patients and reveal the rules of ILR and ILI during cell fate specification.