The atypical cadherin flamingo regulates synaptogenesis and helps prevent axonal and synaptic degeneration in Drosophila

Abstract

The formation of synaptic connections with target cells and maintenance of axons are highly regulated and crucial for neuronal function. The atypical cadherin and G-protein-coupled receptor Flamingo and its orthologs in amphibians and mammals have been shown to regulate cell polarity, dendritic and axonal growth, and neural tube closure. However, the role of Flamingo in synapse formation and function and in axonal health remains poorly understood. Here we show that fmi mutations cause a significant increase in the number of ectopic synapses on muscles and result in the formation of novel en passant synapses along axons, and unique presynaptic varicosities, including active zones, within axons. fmi mutations also cause defective synaptic responses in a small subset of muscles, an agedependent loss of muscle innervation and a drastic degeneration of axons in 3 rd instar larvae without an apparent loss of neurons. Neuronal expression of Flamingo rescues all of these synaptic and axonal defects and larval lethality. Based on these observations, we propose that Flamingo is required in neurons for synaptic target selection, synaptogenesis, the survival of axons and synapses, and adult viability. These findings shed new light on a possible role for Flamingo in progressive neurodegenerative diseases.

FatJ acts via the Hippo mediator Yap1 to restrict the size of neural progenitor cell pools

“…Our studies complement and support studies that document a role for cadherin genes in early neural tube development, for example, showing that N-cadherin is required to maintain the integrity of the neuroepithelium (Lele et al, 2002). In addition, our studies highlight the temporal effects of cadherins in neural tube development: our screen did not reveal early roles for cadherins previously shown to affect later development of the spinal cord, including late migration of neural crest cells (Coles et al, 2007), sorting of cell pools (Price et al, 2002) and synapse formation (Bao et al, 2007).…”

Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets

“…Drosophila studies provide us with a distinct function view of Flamingo/Starry night as a core planar polarity protein [64] . Its functions include regulating dendrite extension from sensory neurons [65,66] , modulating target selection by photoreceptor axons [67] , accelerating axon advance from sensory and motor neurons [68] , and limiting ectopic neuromuscular junction formation and maintenance of motor axon terminals [69] . Gene knockout and knockdown of 7TM-cadherins has also confirmed this observation in vertebrates.…”

Planar cell polarity genes, Celsr1-3, in neural development

“…In addition, Flamingo is reported to regulate synaptogenesis and to prevent axonal and synaptic degeneration in Drosophila [29] . In normal larvae, the intersegmental nerves travel towards dorsal muscles showing a "beads-ona-string" pattern of synapses extending along the surface of these muscles.…”