Developmental Axon Pruning Requires Destabilization of Cell Adhesion by JNK Signaling

Abstract

Developmental axon pruning is essential for normal brain wiring in vertebrates and invertebrates. How axon pruning occurs in vivo is not well understood. In a mosaic loss-of-function screen, we found that Bsk, the Drosophila JNK, is required for axon pruning of mushroom body γ neurons, but not their dendrites. By combining in vivo genetics, biochemistry, and high-resolution microscopy, we demonstrate that the mechanism by which Bsk is required for pruning is through reducing the membrane levels of the adhesion molecule Fasciclin II (FasII), the NCAM ortholog. Conversely, overexpression of FasII is sufficient to inhibit axon pruning. Finally, we show that overexpressing other cell adhesion molecules, together with weak attenuation of JNK signaling, strongly inhibits pruning. Taken together, we have uncovered a novel and unexpected interaction between the JNK pathway and cell adhesion and found that destabilization of cell adhesion is necessary for efficient pruning.

dMyc is required in retinal progenitors to prevent JNK-mediated retinal glial activation

“…Recently, JNK activity was shown to be important for neuron-glia crosstalk upon neuronal damage in the Drosophila embryonic CNS [63], Drosophila developmental axon pruning [64] but also in mammalian Schwann cells in response to axonal injury [65,66]. Thus, we tested if Myc function in limiting the extent of glia migration is associated to a role in modulating JNK activation during retinal development.…”

“…Activation of JNK in eye progenitors was sufficient to activate Jra/Kayak (c-Jun/c-fos homologues) and trigger non-autonomous glia migration. Interestingly, JNK function in developmental axon pruning and injured axons has been described either as deleterious, through the induction of axonal degradation [102–106] or beneficial, through the activation of axonal regeneration [63,64,107–109]. JNK activation is essential for phagocytosis and autophagy both in Drosophila glia [63,110], mammalian astrocytes [111], Schwann cells [66,112,113], microglia [114] as well as in non-glial cells types [115,116].…”

TheDrosophilachromodomain protein Kismet activates steroid hormone receptor transcription to govern axon pruning and memoryin vivo

“…We generated MARCM clones with homozygous kis LM27 MBs as previously described and aged the adults for 5 days after eclosion. We then immunostained the adult brains with anti-FASII, a transmembrane cell adhesion protein, which is differentially expressed in the separate populations of MB neurons (Bornstein et al, 2015;Stewart and McLean, 2004). FASII expression is lowest in the early born gamma neurons and highest in the late born alpha/beta neurons; therefore, the appearance of GFP labeled MARCM axons in the dorsal lobe that are weakly or unstained for FASII would constitute aberrant unpruned axons that persisted into adulthood (Bornstein et al, 2015).…”

“…We then immunostained the adult brains with anti-FASII, a transmembrane cell adhesion protein, which is differentially expressed in the separate populations of MB neurons (Bornstein et al, 2015;Stewart and McLean, 2004). FASII expression is lowest in the early born gamma neurons and highest in the late born alpha/beta neurons; therefore, the appearance of GFP labeled MARCM axons in the dorsal lobe that are weakly or unstained for FASII would constitute aberrant unpruned axons that persisted into adulthood (Bornstein et al, 2015). Compared to control MBs, kis LM27 MARCM clones had significantly more weakly stained and/or unstained FASII GFPpositive axons outside the dorsal lobe bundle, indicating that pruning is in fact prevented and not delayed in this mutant (Figs.…”

A Fasciclin 2 functional switch controls organ size in Drosophila

“…The JNK signaling pathway controls apoptosis and has been propossed to interact with Fas2 during neural differentiation in pupa. [20]. To test the involvement of this signaling pathway in the fas2 phenotype during imaginal disc growth, we induced the inhibition of JNK (Bsk) activity in the wing of MS1096-Gal4/+; UAS-fas2 RNAi /UAS-bsk RNAi and in the eye disc of eyeless-driven UAS-fas2 RNAi /UAS-bsk RNAi FLP-OUT individuals.…”