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Studying the composition and interaction patterns of cell surface proteins can help to understand issues such as
the development, function, maintenance, and aging of neural circuits.
Single-cell sequencing and other technologies can effectively collect and analyze RNA in cells, but due to the influence of translation and transport efficiency and protein stability, the transcriptome is difficult to effectively represent the real situation of cell surface proteins.
On the other hand, in the past, direct research on the cell surface proteome required chemical labeling and other treatments after breaking the tissue into free cells, and the lysis of the tissue itself would change the proteins
on the cell surface.
On October 10, 2022, the Luo Liqun team and collaborators from Stanford University and the Howard Hughes Medical Institute in the United States published an article entitled In situ cell-type-specific cell-surface proteomic profiling in mice in the journal Neuron
。 Andrew Shuster and Li Jiefu, doctoral students in Luo's lab, are co-first authors
of this paper.
This paper introduces a method of adjacent enzyme labeling on mice to realize the surface proteome labeling analysis of specific types of cells, and uses this technology to depict the quantitative changes of Purkinje cell surface proteome during cerebellar development in mice, and discovers the important role of
Armh4 molecule in dendritic morphogenesis of Purkinje cells.
In 2020, Luo Liqun, Alice Ting, Li Jiefu, Han Shuo and collaborators developed a high-spatiotemporal resolution quantitative method for cell surface proteomics (see BioArt report: Cell | Luo Liqun/Alice Ting collaborated to use in situ proteomics to reveal the regulatory molecules of neuronal connections in the brain) and applied it to the study of olfactory neural circuit development in fruit flies, and discovered many new molecular regulatory neural circuits
.
Subsequently, this year, the team used this technique to discover the cell surface protein combination coding pattern controlled by transcription factors (see BioArt report: Neuron | Luo Liqun/Xie Qijing/Li Jiefu et al.
found transcription factor-controlled cell surface protein combination coding).
This technique can complete the in situ labeling analysis of the surface proteome of specific cell types at the biological tissue level, and this paper further generalizes the technology to mammalian organisms, realizing cell surface labeling in a variety of tissues and organs in mice (see figure below, green fluorescence channel shows biotin signal on cell surface).
Using this technique, the authors labeled and quantified the surface proteomics of mouse cerebellar Purkinje cells located at different developmental stages (15 and 35 days after birth
).
。 The results of cell surface protein composition in Purkinje during development and after maturation were greatly changed by cell surface protein composition after isolation and purification, and the transcriptome results obtained by single-cell sequencing method were also different, further indicating that the cell surface proteome was subject to extensive post-translational regulation
.
The authors further take the Armh4 protein enriched in the developmental stage of Purkinje cells as an example to explore the role
of cell surface proteins in dendritic development of Purkinje cells through gene knockout and overexpression.
The interesting result is that both knockout and overexpression of Armh4 will lead to dendritic hypoplasia
.
Based on the structural analysis of the Armh4 molecule, the authors edited the intracellular domain of the Armh4 molecule, and finally showed that the intracellular domain of the molecule is involved in the transmission of downstream signals, and the related regulatory process may be related to the endocytosis process (see figure below).
In this paper, the surface proteome labeling technology developed by Luo Liqun's team in Drosophila has been successfully translated into mammalian models, and the cell surface protein labeling technology developed in this paper has a wide application prospect in cell surface proteomics
research in nerve, tumor, immune and other systems.
The transgenic animal model will be available from The Jackson Laboratory, and the associated plasmid will be available
from Addgene.
Dr.
Li Jiefu is currently the head of the research group at the Howard Hughes Medical Institute's Chania Research Park (HHMI Janelia), where the laboratory combines molecular tool development, high-resolution imaging and other technical means to study cell surface signals
in the nervous system and immune system.
Postdocs in structural biology (Cryo-ET/EM, integrative structural biology) and chemical biology are welcome to join ( style="font-size: 15px;color: rgb(63, 63, 63);" _mstmutation="1" _istranslated="1">
Original link: 00864-9
Pattern maker: Eleven
References
1.
Li, J.
, et al.
(2020).
Cell-surface proteomic profiling in the fly brain uncovers wiring regulators.
Cell, 180(2), 373-386.
2.
Xie, Q.
, et al.
(2022).
Transcription factor Acj6 controls dendrite targeting via a combinatorial cell-surface code.
Neuron, 110(14), 2299-2314.
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