Newswise — One of the most complex brain regions of the mammalian nervous system, the hypothalamus contains an astonishing heterogeneity of neurons that regulate endocrine, autonomic, and behavioral functions. It not only regulates food consumption, water intake, body temperature, circadian rhythm, and sleep to maintain the survival of individual organisms, but also controls the onset of puberty and reproductive behavior to maintain the population. breeder.
“What Triggers Puberty” is one of the 125 Big Questions Posed in the 125th Anniversary Issue of Sciences magazine. Researchers led by Prof. WU Qingfeng from the Institute of Developmental Genetics and Biology of the Chinese Academy of Sciences have revealed that the developmental programming of the onset of puberty is dependent on TBX3. They have also discovered new rules for lineage progression, which operate through neuronal differentiation during the development of the hypothalamus.
The results were published in Progress of science November sixteen.
In this study, Prof. WU’s group discovered 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 collection of neuropeptidergic neurons in the brain, among which hypothalamic KNDy neurons represent an indispensable cell subtype that controls the onset of puberty. Although hypothalamic neuronal progenitors and neuronal precursors along the lineage hierarchy have been proposed to adopt a cascading 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 shorter forelimbs, defective development of the mammary gland, and genital abnormalities. It is notable that most patients with UMS show a delayed onset of puberty.
According to the researchers, at the organism level, genetic ablation of tbx3 it significantly delays the onset of puberty in animals and disturbs the estrous cycle of female mice. At the cellular level, TBX3 plays an important role in establishing and maintaining the fate of hypothalamic KNDy neurons. Furthermore, at the molecular level, TBX3 regulates gene transcription through phase separation, thereby inducing neuropeptide expression in hypothalamic neurons.
important, multiple TBX3 Mutants identified in UMS patients fail to form phase-separation condensates and are unable to efficiently regulate neuropeptide expression, providing a pathological mechanism underlying delayed puberty in UMS patients.
Furthermore, Prof. WU aimed to answer how the neuronal lineage progresses during the development of the hypothalamus under physiological and pathological conditions. He and his colleagues used an unprecedented strategy of cell type alignment by comparing single-cell data sets from lineage tracing and genetically engineered mice, and revealed two lineage-independent rules: intralineage retention (ILR) and interlineage interaction (ILI), which regulates the lineage. progression in pathological conditions.
Collectively, this study uncovers the cellular and molecular mechanisms that underlie how TBX3 The mutations interfere with the onset of puberty in UMS patients and reveal the rules of ILR and ILI during cell fate specification.
This work was funded by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the CAS Strategic Priority Research Program, and the Beijing Municipal Commission for Science and Technology.