Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1.

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.

N'-(3-Bromo-5-chloro-2-hy-droxy-benzyl-idene)-2H-1,3-benzodioxole-5-carbo-hydrazide.

The asymmetric unit of the title hydrazone compound, C(15)H(10)BrClN(2)O(4), contains two independent mol-ecules. The dihedral angles between the benzene rings are 38.7 (3)° in one mol-ecule and 24.3 (3)° in the other. Both mol-ecules exist in trans conformations with respect to the C=N double bonds of the central methyl-idene units. Intra-molecular O-H⋯N contacts are observed in both mol-ecules, forming S(6) rings. In the crystal, mol-ecules are linked through N-H⋯O hydrogen bonds into chains along the a axis.