ORCID Profile
0000-0002-3056-8137
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Publisher: Elsevier BV
Date: 12-2023
Publisher: Public Library of Science (PLoS)
Date: 11-2022
DOI: 10.1371/JOURNAL.PBIO.3001856
Abstract: Feingold syndrome type 1, caused by loss-of-function of MYCN, is characterized by varied phenotypes including esophageal and duodenal atresia. However, no adequate model exists for studying the syndrome’s pathological or molecular mechanisms, nor is there a treatment strategy. Here, we developed a zebrafish Feingold syndrome type 1 model with nonfunctional mycn , which had severe intestinal atresia. Single-cell RNA-seq identified a subcluster of intestinal cells that were highly sensitive to Mycn, and impaired cell proliferation decreased the overall number of intestinal cells in the mycn mutant fish. Bulk RNA-seq and metabolomic analysis showed that expression of ribosomal genes was down-regulated and that amino acid metabolism was abnormal. Northern blot and ribosomal profiling analysis showed abnormal rRNA processing and decreases in free 40S, 60S, and 80S ribosome particles, which led to impaired translation in the mutant. Besides, both Ribo-seq and western blot analysis showed that mTOR pathway was impaired in mycn mutant, and blocking mTOR pathway by rapamycin treatment can mimic the intestinal defect, and both L-leucine and Rheb, which can elevate translation via activating TOR pathway, could rescue the intestinal phenotype of mycn mutant. In summary, by this zebrafish Feingold syndrome type 1 model, we found that disturbance of ribosomal biogenesis and blockage of protein synthesis during development are primary causes of the intestinal defect in Feingold syndrome type 1. Importantly, our work suggests that leucine supplementation may be a feasible and easy treatment option for this disease.
Publisher: Elsevier BV
Date: 04-2023
Publisher: Cold Spring Harbor Laboratory
Date: 29-05-2023
DOI: 10.1101/2023.05.29.542713
Abstract: During gastrulation, the mesendoderm is firstly specified by morphogens such as Nodal, and then segregates into endoderm and mesoderm in a Nodal concentration-dependent manner. However, so far, the underlying mechanism of this segregation remains unclear. Here, taking zebrafish prechordal plate (PP) and endoderm (Endo) as research model, using single cell multi-omics and live imaging analyses, we show that anterior endodermal progenitors originate directly from prechordal plate. Deconvolution analysis for bulk RNA-seq datasets of Nodal-injected explants reveals that the specification of anterior endoderm from PP was determined by a relatively lower Nodal signaling. And a single-cell transcriptomic trajectory analysis of wild-type, ndr1 knockdown and lefty1 knockout Nodal explants confirms the ersification of Endo fate from PP progenitors. Genstoe Ontology (GO) enrichment analysis indicates that chromatin organization potentially underlies the segregation of endodermal cell fate from PP. A further single-cell ATAC and RNA sequencing analysis suggests a positive correlation between Nodal activity and chromatin openness. We then identify two transcriptional regulators, gsc and ripply1 , which are differentially activated in PP and Endo, and manipulation of their expression levels tilts the cell fate decision between these two lineages. Collectively, our study suggests that different levels of Nodal activity promote transcriptional ersification between PP and Endo potentially through modulation of chromatin states, which eventually leads to ersification in cell fate decisions.
No related grants have been discovered for Tao Cheng.