Study reveals new rules for bloodline progression

The hypothalamus, one of the most complex brain regions in the mammalian nervous system, contains an astonishing heterogeneity of neurons that regulate endocrine, autonomic and behavioral functions. It not only regulates food consumption, water consumption, body temperature, circadian rhythm, and sleep to maintain the survival of individual organisms, but also controls the onset of puberty and reproductive behavior to sustain the reproductive population.

“What triggers puberty” is one of the 125 big questions asked in the 125th anniversary edition of Science magazine. Researchers led by Professor WU Qingfeng from the Chinese Academy of Sciences’ Institute of Genetics and Developmental Biology have revealed that the developmental programming of onset of puberty is dependent on TBX3. They also discovered new rules of lineage progression, which work through neuronal differentiation during development of the hypothalamus.

The results were published in Scientists progress in Nov 16.

In this study, Professor 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 is made up of a heterogeneous collection of neuropeptidergic neurons in the brain, among which the hypothalamic KNDy neurons represent an indispensable cellular subtype controlling the onset of puberty. Although it has been proposed that hypothalamic neural progenitors and neural precursors along the lineage hierarchy adopt a cascade diversification strategy to generate extreme neural diversity, the cellular logic to specify neuroendocrine neuron subtype is not clear.

Previous genetic studies suggest that genetic mutations in TBX3 cause ulnar-mammary syndrome (UMS), characterized by shortened forelimbs, defective development of the mammary gland and genital abnormalities. It should be noted that most patients with MSU have a delayed onset of puberty.

According to the researchers, at the level of the organism, the genetic ablation of tbx3 significantly delays the onset of puberty in animals and disrupts 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. Moreover, at the molecular level, TBX3 regulates gene transcription by phase separation, thereby inducing the expression of neuropeptides in hypothalamic neurons.

Above all, several TBX3 mutants identified in UMS patients fail to form phase-separated condensates and cannot effectively regulate neuropeptide expression, providing a pathological mechanism underlying the delay of puberty in UMS patients.

In addition, Prof. WU aimed to address neuronal lineage progression during development of the hypothalamus under physiological and pathological conditions. He and his colleagues used an unprecedented cell type alignment strategy by comparing single-cell datasets from lineage tracing and genetically manipulated mice, and revealed two lineage-independent rules – intra- lineage (ILR) and inter-lineage interaction (ILI) -; regulate lineage progression under pathological conditions.

Collectively, this study reveals the cellular and molecular mechanisms underlying how TBX3 the mutations interfere with the onset of puberty in UMS patients and reveal the rules of ILR and ILI in cell fate specification.