For this, they dissected 9,000 brains

Text ｜ "China Science News" reporter Feng Lifei

The brain is like an extremely precise communication network. They form a specific ring through the connection between neurons, perceive the external world, and direct the behavior of people and animals.

Scientists have found that the human brain has about 86 billion neurons, and thousands of synapses are connected between each two neurons. The total connection can reach 1014.

"The establishment of precision connections between neurons is vital to survival of people and other animals. Once an error occurs, a neurological disorder is formed, and diseases such as intellectual obstacles and autism spectrum disorders will occur." Said the Journal of China.

So, how to establish a precise connection between the brain neurons? In the recent research on the journal "Neuron", Xie Qijing's Stanford University and Howard Hughes Medical Research Institute Professor Luo Liqun's research team found two proteins of neuroplastin " "Inner and outer" team executes accurate connection passwords.

"Inner Ying and Outside" issuing order ordering

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Through decades of research, scientists have a deep understanding of the main protein structure of the brain and the general outline of the synapses. , And establish a specific connection with other neurons.

Most of these molecules known are two types of proteins: transcription proteins (or transcription factor) and cell surface proteins.

The transcription factor is located in the nucleus and is known as the "central commander", known as the fate of cells, and determines the shape and function of the cells; the protein located on the surface of the cell membrane is the executor of the command. "Scientists often guess that the transcription factors control the precise connection between neurons by controlling the expression of cell surface proteins, but it is not clear that the transcription factors are ordained by regulating the surface protein of which cells." Xie Qijing said.

In the new research, the researchers took the olfactory sensory transcription factor ACJ6 as an example to show how the "central commander" can control the accurate connection of different neurons by regulating the expression of cell surface protein in different combinations. Xie Qijing and Luo Liquan Lab, Li Jiefu, is the first author of this article.

About 20 years ago, the Luo Liquan team found that ACJ6 could control some precise connections of tactile projection neurons. However, at that time, due to the lack of the method of directly measured the surface protein expression of specific cell groups, it was impossible to further know how ACJ6 and other transcription factors controlled the specificity of nerve connection through the protein on the cell surface.

Faced with this challenge, Li Jiefu and collaborators developed a method of marking cell surface protein in 2020, which can use mass spectrometers to determine the "identity" of these proteins. More importantly, this technology can directly perform high -precision albumin marks, enrichment and analysis of the specified cell type surface protein set in the complete fruit flies, so that the analysis of the surface protein group and the corresponding neurons can be connected as possible. Essence

Utilizing this technology, researchers revealed many molecules executing the AJC6 command in the new research. For the first time, the specificity of the nerve connection was proved by the experiment and controlled by the combination. "A reviewer told us that this study added more information about all the papers about this theme before," Luo Liqun said in an interview with the media.

Looking for the "password" of fruit flies brain

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The result is gratifying, but the process is not simple.

"In different neurons, a transcription factors specify their specific connections by regulating the same or different cell surface proteins. For this reason, we need to knock out or do not express these genes to observe its sense of smelling neurons to the olfactory neurons. The influence, see if you can still establish the correct connection. "Xie Qijing explained. Researchers chose to use the model animal fruit flies to find the "password". The brain of the fruit flies seems very small, but there are 200,000 neurons and over 10 million synapses. Determining the role of a specific protein in one of the cells is not as difficult as Haidilao needle.

In order to get enough samples, Xie Qijing spent several months with the help of the team to dissect more than 9,000 fruit flies' brains. In the experiments, they conducted quantitative analysis of the surface protein group in the wild type (ACJ6) and mutant (lost ACJ6), respectively, revealing many molecules that execute the ACJ6 connection indication.

Interestingly, in addition to cell adhesion molecules, they also found some proteins that are traditionally considered to only mediate neuronal functions, such as mechanical sensitive ion channel Piezo, and also play a key regulatory role in ensuring accurate nerve connections.

Last year, American neurologist Ardem Patapoutian had won the Nobel Prize in Physiology or Medicine because he identified the Piezo family of mammals to feel mechanical power in mammals and found his important role in tactile and physical perception. Now, new studies have found that the mutation of Piezo's mutation will lead to the target of neuronal dendritic errors. "This result shows the function of Piezo independent of a mechanical ion channel for the first time." Xie Qijing said. In order to establish a functional connection between ACJ6 and the surface protein that regulates in the target of tree dendritic, the researchers knocked the transcription factors in the projection neuron, and in these neurons Surface protein. The results show that among different neurons types, ACJ6 uses the surface protein expression of different combinations to specify this type of neuron -specific target.

"This shows that in different neurons types, the" center commander of the transcription factor 'to complete the instructions by controlling the surface proteins of different combinations, forming a specific and very sensitive connection. You can control a lot of different nerve connections. "Xie Qijing said.

Better help disease prevention and treatment

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In this study, the author also demonstrated the genetic interaction mode between neuron surface proteins: adding, subtraction, and synergy.

In addition to neural development, they said that the framework of "transcription factor -cell surface protein -physiological function" exists in all biology processes involving cells and environmental exchanges. Therefore, this research also puts forward a new strategy and method prototype for future research transcription factor functions and mechanisms.

"Although the small fruit flies look very different from humans, their genomes and human genome actually have 60%homologous." Xie Qijing, who just worked in an enterprise, hopes that through these basic research, it can be better to be better Understand the brain of humans and other animals and how they grow and develop, and understand which gene mutations can bring disease, so as to better prevent and treat.

The protein group science technology adopted by this study is not only suitable for neurons, but also can easily expand to other applications. According to reports, Li Jiefu is setting up his own laboratory at the Hughes Institute of Medical Research Park, where he hopes to "use these tools to study the immune system and cancer."

Related thesis information:

https://doi.org/10.1016/j.neuron.2022.04.026

"China Science News" (2022-07-04 The second edition of the original title "9000 fruit flies to reveal how neurons are accurately connected"))

Edit | Zhao Lu

Capture | Zhihai

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