Neurofibromatosis-like phenotype in Drosophila caused by lack of glucosylceramide extension

Abstract

Glycosphingolipids (GSLs) are of fundamental importance in the nervous system. However, the molecular details associated with GSL function are largely unknown, in part because of the complexity of GSL biosynthesis in vertebrates. In Drosophila , only one major GSL biosynthetic pathway exists, controlled by the glycosyltransferase Egghead (Egh). Here we discovered that loss of Egh causes overgrowth of peripheral nerves and attraction of immune cells to the nerves. This phenotype is reminiscent of the human disorder neurofibromatosis type 1, which is characterized by disfiguring nerve sheath tumors with mast cell infiltration, increased cancer risk, and learning deficits. Neurofibromatosis type 1 is due to a reduction of the tumor suppressor neurofibromin, a negative regulator of the small GTPase Ras. Enhanced Ras signaling promotes glial growth through activation of phosphatidylinositol 3-kinase (PI3K) and its downstream kinase Akt. We find that overgrowth of peripheral nerves in egh mutants is suppressed by down-regulation of the PI3K signaling pathway by expression of either dominant-negative PI3K, the tumor suppressor PTEN, or the transcription factor FOXO in the subperineurial glia. These results show that loss of the glycosyltransferase Egh affects membrane signaling and activation of PI3K signaling in glia of the peripheral nervous system, and suggest that glycosyltransferases may suppress proliferation.

Drosophila glia: Few cell types and many conserved functions

“…Wrapping glial morphogenesis depends on Integrin and Laminin signaling (Petley-Ragan et al, 2016;Xie & Auld, 2011;Xie, Gilbert, Petley-Ragan, & Auld, 2014) and requires enzymes controlling sphingolipid biosynthesis (Ghosh et al, 2013). In line with that, a role for the glycosphingolipid synthesis in peripheral glial development was shown in mutants of the glycosyltransferase egghead (Dahlgaard et al, 2012). Nerves lacking egghead show an overgrowth of peripheral glia, possibly via activation of PI3K signaling.…”

“…How growth of the subperineurial glial cells is adjusted to the growing nervous system is not entirely clear. In abdominal nerves, loss of the Egghead (Egh) protein, which is a mannosyltransferase that controls conversion of glucosylceramide to mactosylceramide, causes increased endomitosis which is largely due to aberrant activation of phosphatidylinositol 3‐kinase (PI3K), insulin and FGF‐signaling (Dahlgaard et al, ; Gerdøe‐Kristensen, Lund, Wandall, & Kjaerulff, ). Activity of the Hippo signaling pathway is also regulated by a miRNA ( miR‐285 ) which together with the RNA binding protein Multiple Ankyrin repeats Single KH domain (Mask) establishes a double‐negative feedback loop to suppress polyploidity of the subperineurial glia (Li et al, ).…”

β3GnT8 Regulates Laryngeal Carcinoma Cell Proliferation Via Targeting MMPs/TIMPs and TGF-β1

“…Numerous reports have demonstrated that the expression of MMP-2 and MMP-9 is closely correlated with cell proliferation and process of tumor progression. It has been reported that MMP-2 can regulate growth in stellate cells directly (Dahlgaard et al, 2012). Others have showed that protein kinase D1 inhibits cell proliferation through MMP-2 and MMP-9 in prostate cancer (Biswas et al, 2010).…”

“…The deficiency of LH3 glycosyltransferase activities, especially in the extracellular space, causes growth arrest revealing the importance of LH3 for cell growth and viability (Wang et al, 2009). Loss of the glycosyltransferaseEgghead affects membrane signaling and activation of PI3K signaling in glia of the peripheral nervous system, and suggest that Egghead may suppress proliferation (Dahlgaard et al, 2012). Therefore, this report mainly concerned the relationship between β3GnT8 and cell proliferation behavior.…”

Suppressive Effects of SuHeXiang Wan on Amyloid-β42-Induced Extracellular Signal-Regulated Kinase Hyperactivation and Glial Cell Proliferation in a Transgenic <i>Drosophila</i> Model of Alzheimer’s Disease

“…31) Furthermore, inflammation has been also implicated in the pathogenesis of neurodegenerative disease animal models, including mice and Drosophila. 32,33) These findings have led to the postulation that neuronal inflammation is the cause of neurodegenerative diseases, such as AD, and that anti-inflammation drugs may act as protective agents for the diseases. 34,35) Several drug candidates have been developed to treat AD.…”