The Drosophila Blood-Brain Barrier Adapts to Cell Growth by Unfolding of Pre-existing Septate Junctions

Abstract

Graphical Abstract Highlights d Septate junction (SJ) proteins are stable for days d SJ strands are prefigured during embryogenesis and are unfolded during larval stages d The G-protein coupled receptor Moody suppresses interdigitating cell-cell protrusions d Moody promotes formation of continuous SJ strands SUMMARYThe blood-brain barrier is crucial for nervous system function. It is established early during development and stays intact during growth of the brain. In invertebrates, septate junctions are the occluding junctions of this barrier. Here, we used Drosophila to address how septate junctions grow during larval stages when brain size increases dramatically. We show that septate junctions are preassembled as long, highly folded strands during embryonic stages, connecting cell vertices. During subsequent cell growth, these corrugated strands are stretched out and stay intact during larval life with very little protein turnover. The G-protein coupled receptor Moody orchestrates the continuous organization of junctional strands in a process requiring F-actin. Consequently, in moody mutants, septate junction strands cannot properly stretch out during cell growth. To compensate for the loss of blood-brain barrier function, moody mutants form interdigitating cell-cell protrusions, resembling the evolutionary ancient barrier type found in primitive vertebrates or invertebrates such as cuttlefish.

Lgl cortical dynamics are independent of binding to the Scrib-Dlg complex but require Dlg-dependent restriction of aPKC

“…Understanding how basolateral proteins maintain apical-basal polarity requires approaches to explore their dynamic behavior, which is intimately connected to their function. Dlg and Scrib mobility has been previously studied in the context of septate junctions (Babatz et al, 2018;Oshima and Fehon, 2011). We now compared the dynamics of the basolateral determinants in the lateral domain and dissected the mechanisms of Lgl association to the cortex.…”

Drosophila glia: Few cell types and many conserved functions

“…Moody‐dependent formation of actin‐rich structures along the lateral membrane of the subperineurial glia requires myosin activation and controls blood–brain barrier function (Hatan, Shinder, Israeli, Schnorrer, & Volk, ). Homozygous moody mutants, however, are viable and have only a mildly affected blood–brain barrier (Stork et al, ) due to a compensatory formation of interdigitating cell‐cell protrusions, resembling the evolutionary ancient barrier type found in primitive vertebrates or invertebrates such as cuttlefish (Stork et al, 2018; Babatz, Naffin & Klämbt, ).…”

“…In Drosophila, septate junction complexes show an amazing stability and exist without major remodeling for several days. To cope with the enormous growth of the subperineurial glial cells during development, most septate junctions are preassembled in a folded manner already during embryonic stages which are then stretched out during larval growth (Babatz, Naffin & Klämbt, 2018). To date, more than 20 membrane or membrane-associated proteins are known including the conserved core components NeurexinIV/CASPR and Neuroglian/ NF150 (Faivre-Sarrailh et al, 2004;Hall et al, 2014;Jaspers et al, 2012;Nilton et al, 2010;Oshima & Fehon, 2011;Syed, Krudewig, Engelen, Stork, & Klämbt, 2011;Wu & Beitel, 2004).…”

“…Homozygous moody mutants, however, are viable and have only a mildly affected blood-brain barrier (Stork et al, 2008) due to a compensatory formation of interdigitating cell-cell protrusions, resembling the evolutionary ancient barrier type found in primitive vertebrates or invertebrates such as cuttlefish (Stork et al, 2018;Babatz, Naffin & Klämbt, 2018).…”

To BBB or Not to BBB?

“…One well-studied SJ protein in SPG, Moody, has been shown be required for SJ formation Schwabe et al, 2005), but previous work (Stork et al, 2008) from the group reporting the current study has shown that animals lacking Moody survive with only mild BBB permeability. In moody mutant animals, Babatz et al (2018) show that SJs are established at the early stages but appear less corrugated, more fragmented, and with pre-assembled SJ components frequently found outside of SJ strands. How is barrier function preserved despite these poorly constructed SJs?…”