RESUMEN
Studies on genetic robustness recently revealed transcriptional adaptation (TA) as a mechanism by which an organism can compensate for genetic mutations through activation of homologous genes. Here, we discovered that genetic mutations, introducing a premature termination codon (PTC) in the amyloid precursor protein-b (appb) gene, activated TA of two other app family members, appa and amyloid precursor-like protein-2 (aplp2), in zebrafish. The observed transcriptional response of appa and aplp2 required degradation of mutant mRNA and did not depend on Appb protein level. Furthermore, TA between amyloid precursor protein (APP) family members was observed in human neuronal progenitor cells; however, compensation was only present during early neuronal differentiation and could not be detected in a more differentiated neuronal stage or adult zebrafish brain. Using knockdown and chemical inhibition, we showed that nonsense-mediated mRNA decay (NMD) is involved in degradation of mutant mRNA and that Upf1 and Upf2, key proteins in the NMD pathway, regulate the endogenous transcript levels of appa, appb, aplp1, and aplp2 In conclusion, our results suggest that the expression level of App family members is regulated by the NMD pathway and that mutations destabilizing app/APP mRNA can induce genetic compensation by other family members through TA in both zebrafish and human neuronal progenitors.
Asunto(s)
Precursor de Proteína beta-Amiloide , Degradación de ARNm Mediada por Codón sin Sentido , Pez Cebra , Animales , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Humanos , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , ARN Mensajero/metabolismo , Células-Madre Neurales/metabolismo , Mutación , Animales Modificados GenéticamenteRESUMEN
The intramolecular 1,3-dipolar cycloaddition of isovanillin derived N-aryl hydroxylamines possessing ortho-allylic dipolarophiles affords novel benzo analogues of tricyclic isoxazolidines that can be readily transformed into functionalized lactams, γ-aminoalcohols and oxazepines. The corresponding N-unsubstituted hydroxylamines give rise to tetrahydroisoquinolines. Anxiogenic properties of these compounds are tested in zebra fish.
