Tissue-specific regulation of BMP signaling by Drosophila N-glycanase 1

Abstract

Mutations in the human N-glycanase 1 ( NGLY1) cause a rare, multisystem congenital disorder with global developmental delay. However, the mechanisms by which NGLY1 and its homologs regulate embryonic development are not known. Here we show that Drosophila Pngl encodes an N-glycanase and exhibits a high degree of functional conservation with human NGLY1. Loss of Pngl results in developmental midgut defects reminiscent of midgut-specific loss of BMP signaling. Pngl 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 Drosophila 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 N-glycanase enzyme.

eLife digest

DNA carries the information needed to build and maintain an organism, and units of DNA known as genes contain coded instructions to build other molecules, including enzymes. Sometimes, genes can become faulty and develop mutations that can affect how an embryo develops and lead to diseases. For example, people with mutations in the gene that encodes an enzyme called N-glycanase 1 experience many problems with their nervous system, gut and other organs.

Normally, N-glycanase 1 helps the body remove specific sugar molecules from some proteins in the cells, and is also thought to be important during embryonic development. As an embryo develops, its cells undergo a series of transformations, which is regulated by different molecules and signaling pathways. For example, a pathway known as BMP signaling plays an important role in many tissues. Problems with this pathway can lead to many diseases throughout the body, including the gut, where it helps cells to develop.

Previous research has shown that fruit flies lacking the gene that codes for an equivalent N-glycanase enzyme (which is called Pngl in flies) cannot develop properly into adults. However, until now it was not known what type of cells need the N-glycanase enzyme in any organism, or if NGLY1 is essential for important signaling pathways like BMP signaling. Now, Galeone et al. have used genetically modified flies to test how losing Pngl affected their development.

The results first showed that engineering Pngl-deficient fruit flies to produce the human enzyme eliminated their problems; these flies developed and survived like normal flies. This confirmed that that the human and fly enzymes can perform equivalent roles. Galeone et al. then discovered that Pngl plays two distinct roles in a group of cells that surround the fruit fly’s gut tissue and give rise to the cells that eventually form the muscle layer in the gut. In the larvae, Pngl was required to empty the gut, which is a necessary step before the larvae can develop into an adult. Moreover, Pngl is needed for BMP signaling in the gut, and when flies had the enzyme removed, some parts of their gut could not from properly.

This study will provide a framework to improve our understanding of how BMP signaling is regulated in humans. A next step will be to test if some of the symptoms experienced by patients without a working copy of the gene for N-glycanase 1 are caused by a faulty BMP-signaling system in specific tissues. If this is the case, it could provide new opportunities to treat some of these symptoms.