Basigin Associates with Integrin in Order to Regulate Perineurial Glia andDrosophilaNervous System Morphology

Abstract

The Drosophila nervous system is ensheathed by a layer of outer glial cells, the perineurial glia, and a specialized extracellular matrix, the neural lamella. The function of perineurial glial cells and how they interact with the extracellular matrix are just beginning to be elucidated. Integrin-based focal adhesion complexes link the glial membrane to the extracellular matrix, but little is known about integrin's regulators in the glia. The transmembrane Ig domain protein Basigin/CD147/ EMMPRIN is highly expressed in the perineurial glia surrounding the Drosophila larval nervous system. Here we show that Basigin associates with integrin at the focal adhesions to uphold the structure of the glia-extracellular matrix sheath. Knockdown of Basigin in perineurial glia using RNAi results in significant shortening of the ventral nerve cord, compression of the glia and extracellular matrix in the peripheral nerves, and reduction in larval locomotion. We determined that Basigin is expressed in close proximity to integrin at the glial membrane, and that expression of the extracellular integrinbinding domain of Basigin is sufficient to rescue peripheral glial compression. We also found that a reduction in expression of integrin at the membrane rescues the ventral nerve cord shortening, peripheral glial compression, and locomotor phenotypes, and that reduction in the integrin-binding protein Talin can partially rescue glial compression. These results identify Basigin as a potential negative regulator of integrin in the glia, supporting proper glial and extracellular matrix ensheathment of the nervous system.

Loss of the extracellular matrix protein Perlecan disrupts axonal and synaptic stability duringDrosophiladevelopment

“…Although the morphology of glia involved in wrapping axons and forming the blood brain barrier was not characterized, it would not be surprising if they displayed morphological and functional defects due to disruption of the neural lamella that contributes to axonal injury. Both glia and the neural lamella can signal or interact directly with MNs (Bittern et al, 2021;Edwards et al, 1993;Hunter et al, 2020;Lee and Sun, 2015;Meyer et al, 2014;Stork et al, 2008;Weiss et al, 2022), providing multiple avenues by which loss of Perlecan could disrupt axonal integrity. Disruptions of interactions that Perlecan normally makes with components regulating the spectrin cytoskeleton could also contribute, as aand b-Spectrin localize to MN axons and RNAi against either protein results in synaptic retraction (Pielage et al, 2005).…”

Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis

“…The linked association of CD147 with integrin α6β1 was observed during increased metastasis in human hepatoma cells [121], suggesting a role for CD147 in modulating integrin α6β1 associations, with matricellular protein CCN1, and mechano-sensitivity to senescence or apoptosis [122]. Interestingly, the nullification of the extracellular domain of CD147 reversed associations with integrin β subunits and FA sites, suggesting that the extracellular domain of CD147 binds to integrins to regulate the mechanical tension of the ECM [121,123]. The roles of these mechanotransducer proteins in stress relay, which is involved in myofibroblast differentiation, will become clearer with continued investigation.…”

The Fly Blood-Brain Barrier Fights Against Nutritional Stress

“…In this manner, the neural lamella provides structural support for the CNS, maintaining its shape and stiffness by the action of focal adhesion with the perineurial layer. 34 , 36 - 38 In addition to this structural support, extracellular matrix components secreted by the perineurial glia promote neurogenesis, forming part of the neural stem cell niche. 33 , 39 …”

“…In this manner, the neural lamella provides structural support for the CNS, maintaining its shape and stiffness by the action of focal adhesion with the perineurial layer. 34,[36][37][38] In addition to this structural support, extracellular matrix components secreted by the perineurial glia promote neurogenesis, forming part of the neural stem cell niche. 33,39 The Drosophila Blood-Brain Barrier Acts as the Nutritional Protector of the Brain Drosophila melanogaster, as a holometabolous insect, transitions across 4 main developmental stages: embryo, larva, pupa, and imago (Figure 2A).…”