The seven-pass transmembrane cadherin Flamingo controls dendritic self-avoidance via its binding to a LIM domain protein, Espinas, in Drosophila sensory neurons

Abstract

Members of the Flamingo cadherin family are required in a number of different in vivo contexts of neural development. Even so, molecular identities downstream from the family have been poorly understood. Here we show that a LIM domain protein, Espinas (Esn), binds to an intracellular juxtamembrane domain of Flamingo (Fmi), and that this Fmi-Esn interplay elicits repulsion between dendritic branches of Drosophila sensory neurons. In wild-type larvae, branches of the same class IV dendritic arborization neuron achieve efficient coverage of its two-dimensional receptive field with minimum overlap with each other. However, this self-avoidance was disrupted in a fmi hypomorphic mutant, in an esn knockout homozygote, and in the fmi/esn trans-heterozygote. A functional fusion protein, Fmi:3eGFP, was localized at most of the branch tips, and in a heterologous system, assembly of Esn at cell contact sites required its LIM domain and Fmi. We further show that genes controlling epithelial planar cell polarity (PCP), such as Van Gogh (Vang) and RhoA, are also necessary for the self-avoidance, and that fmi genetically interacts with these loci. On the basis of these and other results, we propose that the Fmi-Esn complex, together with the PCP regulators and the Tricornered (Trc) signaling pathway, executes the repulsive interaction between isoneuronal dendritic branches.

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

“…That ADGRCs (CELSRs) influence neuronal cell adhesion is apparent from studies of axon guidance in insects (Chen and Clandinin, 2008). In distinct organisms, ADGRCs (CELSRs) differentially interact, either genetically or directly, with various proteins, such as Frizzled, Gogo, Espinas, Vangl2, and RhoA, to control axon outgrowth and targeting, as well as dendritic self-avoidance (BergerMuller and Suzuki, 2011;Matsubara et al, 2011;Hakeda and Suzuki, 2013;Huarcaya Najarro and Ackley, 2013;Chai et al, 2014;Qu et al, 2014). These studies give credence to the idea that the function of 7TM-cadherins could be defined by their binding partners in cis (Berger-Muller and Suzuki, 2011).…”

Partial interchangeability of Fz3 and Fz6 in tissue polarity signaling for epithelial orientation and axon growth and guidance

“…The conserved nature of epithelial PCP signaling can be seen in the morphological and molecular similarities between PCP in mammalian epithelia and in the Drosophila cuticle and wing, both of which require Frizzled, Stan/Fmi/Celsr and Vang/Vangl genes, and both of which feature asymmetric PCP protein complexes (Devenport and Fuchs, 2008;Goodrich and Strutt, 2011;Wang et al, 2006b). In Drosophila and C. elegans, Stan/Fmi/Celsr and Frizzled genes have been implicated in axon guidance, branching and target selection, and Drosophila Stan/Fmi has been implicated in self-avoidance in sensory dendrite tiling (Huarcaya Najarro and Ackley, 2013;Lee et al, 2003;Matsubara et al, 2011;Ng, 2012;Senti et al, 2003;Steinel and Whitington, 2009). In view of the subtly different biological activities of Fz3 and Fz6 observed here, it would be interesting to investigate whether specific classes of mutations in Drosophila Stan/Fmi might differentially affect epidermal polarity versus axonal/dendritic pathfinding/target selection/tiling.…”

Dissecting the molecular bridges that mediate the function of Frizzled in planar cell polarity

“…However, their mammalian counterparts have been shown to interact with each other (Devenport and Fuchs, 2008). But Drosophila Vang does interact directly with Pk (Jenny et al, 2003), while a different Pk-related protein, Espinas, appears to interact directly with Stan during neuronal development (Matsubara et al, 2011). Hence, Vang and Pk might form a cis-complex with Stan in epidermal cells, allowing Vang to act directly on Stan and help it form intercellular bridges with Stan Fz .…”