Science sub-journal: Wu Qingfeng/Miyi team reveals developmental programming mechanisms for puberty initiation

The hypothalamus is one of the most complex brain regions of the central nervous system, with highly diverse neurons that control mammalian homeostasis
by regulating autonomic, endocrine and instinctive behavior.
The hypothalamus not only ensures individual survival by regulating individual feeding, drinking, body temperature, sleep, osmotic pressure, circadian rhythm and other functions, but also controls puberty initiation and sexual reproductive ability to ensure population reproduction
.
Although we have a deep understanding of how the hypothalamus regulates food intake, sleep and body temperature, the mechanism by which it is involved in regulating pubertal initiation is still unknown, and this question has been listed by Science as one of
the 125 most cutting-edge scientific problems.
 

On November 17, 2022, Wu Qingfeng's team from the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and the miserly team from the School of Life Sciences of Tsinghua University published an online report entitled Science Advances Hierarchical deployment of Tbx3 dictates the identity of hypothalamic KNDy neurons to control puberty onset
.

This study not only reveals the initiation mechanism of puberty in mammals from the perspective of developmental programming, but also proposes a new paradigm for transcription factors to regulate neuronal phylogeny, which has important reference significance
for subsequent theoretical research.
 

Past genetic studies have shown that mutations in the transcription factor TBX3 can lead to Ulnar-mammary syndrome (UMS) in humans.
It is characterized by defects in breast development and abnormal bone development in the hands and forearms, but most of concern is severe delayed initiation of puberty in patients with UMS
.

In the work of Wu's team, the researchers found that Tbx3 defines a sublineage of the hypothalamus and acts as a destiny determinant to serially regulate the establishment and maintenance of
neuronal fate.

At the animal level, the gene defect of Tbx3 will cause a significant delay in the initiation of puberty in mice, complete disorder of the estrous cycle of female mice, inability of the ovaries to ovulate normally, and eventually cause infertility.
At the cellular level, Tbx3 plays an important role in establishing and maintaining the fate of hypothalamic KNDy neurons, key neurons that regulate pubertal initiation; At the molecular level, the two research teams found that Tbx3 regulates gene transcription through phase separation, thereby inducing the expression
of neuropeptides.
It is worth noting that the multiple TBX3 mutants that cause UMS in humans cannot undergo effective phase separation, and at the same time, they also significantly lose the ability to regulate neuropeptide expression, resulting in symptoms of delayed onset of puberty
.
 

In the theoretical study of hypothalamic lineage establishment and neurogenesis, the researchers compared "lineage-based tracing" with "genetic manipulation-based" Two single-cell transcriptome databases found that fate determinants can regulate the fate of neurons not only in a classical lineage-dependent way, but also in two lineage-independent ways, which the researchers named intra-lineage retention (ILR) and interlineage interactions ( inter-lineage interaction (ILI), both of which may also be accompanied by lineage-independent compensation (lineage, LIC), which together determines the fate
of neurons in the brain during the development of the disease.
 

Figure: Overview
of the study.
a.
Genealogical dependence and lineage-independent fate determination mechanism (ILR, lineage retention; LIC, lineage independent compensation; ILI, lineage interactions), b.
Key advances (TF, transcription factors; UMS, ulnar breast syndrome).

Reviewers agreed during the review process that the study was "very interesting, in-depth, containing new data resources and scientific concepts, completed with very high quality and standards, and likely to have important implications for the field of hypothalamic development.
"
 

In summary, this study takes human genetics as the starting point to reveal the process of Tbx3 sequence regulating the fate of KNDy neurons in the hypothalamus and then inducing puberty initiation, which provides a new perspective
for the developmental programming mechanism of puberty initiation.
The hypothalamic fate regulator is an important regulatory element that determines the occurrence and development of neuronal fate, and the complex multivariate regulatory network behind it is still worth exploring
.
 

Professor Wu Qingfeng of the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences and Assistant Professor Xiaoyi of Tsinghua University are co-corresponding authors of the paper, and doctoral students Shi Xiang (Wu Qingfeng group), Zhuang Yanrong (miserly group) and Chen Zhenhua (Wu Qingfeng group) are the co-first authors
of the paper.
This research has been funded by major projects such as the National Key Research and Development Program, the National Natural Science Foundation of China, the Pilot of the Chinese Academy of Sciences, and the Hundred Talents Program, and also supported by Professor Pei Duanqing of Westlake University, researcher Jiang Danhua of the Institute of Genetics and Development, Chinese Academy of Sciences, and Liu Longqi, dean of Hangzhou BGI Life Science Research Institute
.
 

Paper Link: