Accumulation of Laminin Monomers inDrosophilaGlia Leads to Glial Endoplasmic Reticulum Stress and Disrupted Larval Locomotion

Abstract

The nervous system is surrounded by an extracellular matrix composed of large glycoproteins, including perlecan, collagens, and laminins. Glial cells in many organisms secrete laminin, a large heterotrimeric protein consisting of an ␣, ␤, and ␥ subunit. Prior studies have found that loss of laminin subunits from vertebrate Schwann cells causes loss of myelination and neuropathies, results attributed to loss of laminin-receptor signaling. We demonstrate that loss of the laminin ␥ subunit (LanB2) in the peripheral glia of Drosophila melanogaster results in the disruption of glial morphology due to disruption of laminin secretion. Specifically, knockdown of LanB2 in peripheral glia results in accumulation of the ␤ subunit (LanB1), leading to distended endoplasmic reticulum (ER), ER stress, and glial swelling. The physiological consequences of disruption of laminin secretion in glia included decreased larval locomotion and ultimately lethality. Loss of the ␥ subunit from wrapping glia resulted in a disruption in the glial ensheathment of axons but surprisingly did not affect animal locomotion. We found that Tango1, a protein thought to exclusively mediate collagen secretion, is also important for laminin secretion in glia via a collagen-independent mechanism. However loss of secretion of the laminin trimer does not disrupt animal locomotion. Rather, it is the loss of one subunit that leads to deleterious consequences through the accumulation of the remaining subunits.

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).…”

“…In the absence of the neural lamella, or loss of integrin mediated contact to this structure, the nervous system fails to be condensed in its normal form and rather stays in its original embryonic appearance. In addition, the lack of the neural lamella or its altered stiffness disrupts migration of the perineurial glia (Kim et al, ; Meyer, Schmidt, & Klämbt, ; Pandey, Blanco, & Udolph, ; Petley‐Ragan, Ardiel, Rankin, & Auld, ; Skeath et al, ; Tavares et al, ).…”

“…Color code is as in Figure 1. For further details see text (Kim et al, 2014;Meyer, Schmidt, & Klämbt, 2014;Pandey, Blanco, & Udolph, 2011;Petley-Ragan, Ardiel, Rankin, & Auld, 2016;Skeath et al, 2017;Tavares et al, 2015).…”

The genetics of egg retention and fertilization success inDrosophila: One step closer to understanding the transition from facultative to obligate viviparity

“…; Petley‐Ragan et al. ). Ovaries of LanB2 depleted mutant flies contain aberrant follicle cells and rounded eggs (Diaz de la Loza et al.…”

Unwrapping the unappreciated: recent progress in Remak Schwann cell biology

“…In peripheral nerves, Drosophila wrapping glia ensheath and separate single or small bundles of axons with their membranes within the nerve, similar to the segregation of individual axons by RSCs [43,44]. Recent work suggests that several genes implicated in RSC development, including NRG1 [45] and Laminin [30,46], appear to perform analogous functions, and act through similar molecular mechanisms in Drosophila wrapping glia. Thus, one possible avenue for further exploration into basic RSC biology might be comparative analyses with wrapping glia in Drosophila .…”