The Drosophila wings apart Gene Anchors a Novel, Evolutionarily Conserved Pathway of Neuromuscular Development

Abstract

wings apart (wap) is a recessive, semilethal gene located on the X chromosome in Drosophila melanogaster, which is required for normal wing-vein patterning. We show that the wap mutation also results in loss of the adult jump muscle. We use complementation mapping and gene-specific RNA interference to localize the wap locus to the proximal X chromosome. We identify the annotated gene CG14614 as the gene affected by the wap mutation, since one wap allele contains a non-sense mutation in CG14614, and a genomic fragment containing only CG14614 rescues the jump-muscle phenotypes of two wap mutant alleles. The wap gene lies centromere-proximal to touch-insensitive larva B and centromere-distal to CG14619, which is tentatively assigned as the gene affected in introverted mutants. In mutant wap animals, founder cell precursors for the jump muscle are specified early in development, but are later lost. Through tissue-specific knockdowns, we demonstrate that wap function is required in both the musculature and the nervous system for normal jump-muscle formation. wap/CG14614 is homologous to vertebrate wdr68, DDB1 and CUL4 associated factor 7, which also are expressed in neuromuscular tissues. Thus, our findings provide insight into mechanisms of neuromuscular development in higher animals and facilitate the understanding of neuromuscular diseases that may result from misexpression of muscle-specific or neuron-specific genes.

Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua

“…One of the prominent Cic interactors identified with high confidence in both cultured cells and embryos was Wap (also known as Riquiqui) (Fig. 1A and Dataset S1) (20,21). Wap binds to the kinase Mnb (19,20), and this interaction is…”

“…Here, we present the identification of the kinase Minibrain (Mnb) (19,20) and an adaptor protein, Wings Apart (Wap) (20,21), as Cic regulators that cooperate to phosphorylate Cic and restrict its repressor activity. We show that Mnb/Wap and ERK target different regions of the Cic protein for phosphorylation, and that inhibition of Cic activity by Mnb and Wap is required for the growth of several organs and for correct patterning of the wing.…”

DCAF7/WDR68 is required for normal levels of DYRK1A and DYRK1B

“…In adenovirus and HPV infection models, WDR68 facilitates substrate recruitment to DYRK1A [17] to suppress cell growth and transformation via phosphorylation of the E1A and E6 proteins, respectively [43–46]. In Drosophila , the genes orthologous to Dyrk1a ( minibrain ) and Wdr68 ( wings apart ) similarly interact to phosphorylate and inhibit the transcriptional repressor capicua thereby enabling proper growth and patterning of several organ systems [47, 48].…”

The adaptor protein DCAF7 mediates the interaction of the adenovirus E1A oncoprotein with the protein kinases DYRK1A and HIPK2

“…Downregulation of dyrk1b induced similar defects in endoderm formation as reported for wdr68 mutant animals, supporting a functional interaction of these proteins in zebrafish development 20 . The DCAF7 ortholog in Drosophila , CG14614 (official gene symbol wap , wings apart, also called riq , riquiqui), is essential for normal wing-vein patterning and development of the adult jump muscle 21 . CG14614 associates with the Drosophila DYRK1 ortholog, MNB (encoded by the minibrain gene, mnb ), and both genes were shown to control normal wing and leg growth by modulating the Salvador-Wart-Hippo (SWH) pathway 22 .…”