Tissue-specific regulation of BMP signaling by <i>Drosophila N</i>-glycanase 1.

Abstract

Mutations in the human <i>N-</i>glycanase 1 (<i>NGLY1</i>) cause a rare, multisystem congenital disorder with global developmental delay. However, the mechanisms by which <i>NGLY1</i> and its homologs regulate embryonic development are not known. Here we show that <i>Drosophila Pngl</i> encodes an <i>N</i>-glycanase and exhibits a high degree of functional conservation with human NGLY1. Loss of <i>Pngl</i> results in developmental midgut defects reminiscent of midgut-specific loss of BMP signaling. <i>Pngl</i> mutant larvae also exhibit a severe midgut clearance defect, which cannot be fully explained by impaired BMP signaling. Genetic experiments indicate that Pngl is primarily required in the mesoderm during <i>Drosophila</i> development. Loss of Pngl results in a severe decrease in the level of Dpp homodimers and abolishes BMP autoregulation in the visceral mesoderm mediated by Dpp and Tkv homodimers. Thus, our studies uncover a novel mechanism for the tissue-specific regulation of an evolutionarily conserved signaling pathway by an <i>N</i>-glycanase enzyme.