ABSTRACTMutations in the gene encoding the ubiquitously expressed RNA-binding protein ZC3H14 result in a non-syndromic form of autosomal recessive intellectual disability. Studies in Drosophila have defined roles for the ZC3H14 ortholog, Nab2 (aka Drosophila Nab2 or dNab2), in axon guidance and memory due in part to interaction with a second RNA-binding protein, the fly Fragile X homolog Fmr1, and coregulation of shared Nab2-Fmr1 target mRNAs. Despite these advances, neurodevelopmental pathways regulated by Nab2 remain poorly defined. Structural defects in Nab2 null brains resemble defects observed upon disruption of the planar cell polarity (PCP) pathway, which regulates planar orientation of static and motile cells. A kinked bristle phenotype in surviving Nab2 mutant adults additionally suggests a defect in F-actin polymerization and bundling, which is also a PCP-regulated processes. To test for Nab2-PCP genetic interactions, a collection of PCP loss-of-function alleles was screened for modification of a rough-eye phenotype produced by Nab2 overexpression in the eye (GMR-Nab2) and subsequently for modification of Nab2 null phenotypes. Multiple PCP alleles dominantly modify GMR-Nab2 eye roughening and a subset of these alleles also rescue low survival and thoracic bristle kinking in Nab2 zygotic nulls. Moreover, alleles of two X-linked PCP factors, dishevelled (dsh) and β amyloid protein precursor-like (Appl), rescue GMR-Nab2 eye roughening in male progeny derived from hemizygous dsh or Appl mutant fathers, suggesting an additional effect inherited through the male germline. These findings demonstrate a consistent pattern of Nab2-PCP genetic interactions that suggest molecular links between Nab2 and the PCP pathway in the developing eye, wing and germline.
The Conserved, Disease-Associated RNA Binding Protein dNab2 Interacts with the Fragile X Protein Ortholog in Drosophila Neurons