RESUMEN
Here we report a human intellectual disability disease locus on chromosome 14q31.3 corresponding to mutation of the ZC3H14 gene that encodes a conserved polyadenosine RNA binding protein. We identify ZC3H14 mRNA transcripts in the human central nervous system, and we find that rodent ZC3H14 protein is expressed in hippocampal neurons and colocalizes with poly(A) RNA in neuronal cell bodies. A Drosophila melanogaster model of this disease created by mutation of the gene encoding the ZC3H14 ortholog dNab2, which also binds polyadenosine RNA, reveals that dNab2 is essential for development and required in neurons for normal locomotion and flight. Biochemical and genetic data indicate that dNab2 restricts bulk poly(A) tail length in vivo, suggesting that this function may underlie its role in development and disease. These studies reveal a conserved requirement for ZC3H14/dNab2 in the metazoan nervous system and identify a poly(A) RNA binding protein associated with a human brain disorder.
Asunto(s)
Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiología , Discapacidad Intelectual/genética , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/fisiología , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Sistema Nervioso Central/fisiología , Mapeo Cromosómico , Cromosomas Humanos Par 14/genética , Estudios de Cohortes , Consanguinidad , Secuencia Conservada , Drosophila melanogaster/genética , Drosophila melanogaster/fisiología , Evolución Molecular , Femenino , Vuelo Animal/fisiología , Técnicas de Silenciamiento del Gen , Genes Recesivos , Hipocampo/metabolismo , Humanos , Irán , Masculino , Modelos Animales , Datos de Secuencia Molecular , Linaje , Proteínas de Unión a Poli(A) , ARN Mensajero/genética , ARN Mensajero/metabolismo , Homología de Secuencia de Aminoácido , Adulto Joven , Dedos de Zinc/genéticaRESUMEN
The reproducible pattern of organismal growth during metazoan development is the product of genetically controlled signaling pathways. Patterned activation of these pathways shapes developing organs and dictates overall organismal shape and size. Here, we show that patches of tissue that are mutant for the Drosophila Tsg101 ortholog, erupted, cause dramatic overproliferation of adjacent wild-type tissue. Tsg101 proteins function in endosomal sorting and are required to incorporate late endosomes into multivesicular bodies. Drosophila cells with impaired Tsg101 function show accumulation of the Notch receptor in intracellular compartments marked by the endosomal protein Hrs. This causes increased Notch-mediated signaling and ectopic expression of the Notch target gene unpaired (upd), which encodes the secreted ligand of the JAK-STAT pathway. Activation of JAK-STAT signaling in surrounding wild-type cells correlates with their overgrowth. These findings define a pathway by which changes in endocytic trafficking can regulate tissue growth in a non-cell-autonomous manner.