To research and establish a precise regulatory system for human stem cell protein and effectively si
Protein dose level will directly affect cell fate and disease occurrence. The same gene, such as FOXG1, can cause a variety of symptoms by varying the dose of the protein due to different types of mutations. Because to knockout the tradition and knockdown strategies are difficult to precisely regulate the protein expression level, the study on the effect of dose difference on FOXG1 syndrome and other similar proteins on diseases is slow. Human pluripotent stem cell (hPSCs) differentiation can mimic early human development and related diseases. To regulatory proteins in hPSCs and differentiated cells precisely dose, through the use of small molecules in hPSCs CRISPR/Cas9 drugs (ASV) sensitive down to solve the stator (degron), and coupling target protein gene, institute of zoology, Chinese academy of sciences/institute of stem cell and regenerative medicine innovation team built a inducible, reversible protein dosage control system precision, and can control target protein dose by ASV concentration accurately. For the first time, the team used this system to precisely regulate multiple endogenous genes in mammals, and combined with hESC neural differentiation system to induce phenotypes such as microcephaly and GABA interneuronal development disorder, effectively simulating FOXG1 syndrome. More importantly, the team found that two dose thresholds of FOXG1, below 60%, resulted in vte formation and delayed GABA interneuron development, while less than 30% failed to form vte and GABA interneurons. These findings lay an important foundation for understanding the phenotypic diversity of FOXG1 syndrome patients and establishing new therapeutic strategies.
The study was published online February 25 in Nature Communications, an international academic journal. The study was conducted by the institute of animal sciences/institute for innovation in stem cell and regenerative medicine. Doctoral students zhu wenliang, zhang boya and graduate student li mengqi are the co-first authors of the paper, and researchers hu baoyang, li wei and zhou qi are the co-corresponding authors of the paper. The research was supported by key projects of the Chinese academy of sciences, the national natural science foundation of China and major science and technology projects in Beijing.
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