Synapse Formation
Establishment of the correct neural circuitry requires growing axons to recognize the appropriate cells as synaptic partners. The photoreceptors that mediate color vision provide us with a simple system in which to examine this process, as photoreceptors that respond to different wavelengths of light project to different target layers in the brain. We have found that the receptor tyrosine phosphatase LAR and its interacting proteins, the Liprins, are required for ultraviolet-sensitive photoreceptors to form synapses with the correct partners, and that LAR signals by a phosphatase-independent mechanism in this process (Hofmeyer et al., 2006; Hofmeyer et al., 2009; Astigarraga et al., 2010). Using a genetic screen, we have identified a novel CUB domain protein, Lost and found (Loaf), that is required for UV-sensitive photoreceptor axon targeting, but only when it is also expressed by other cells in the brain (Douthit et al., in preparation). Our hypothesis is that R7 uses Loaf to compete with other neurons in the brain for access to its target layer. We are also investigating the function of Plexin A, which is necessary to subdivide the layers of the brain to create distinct target layers for photoreceptors that respond to different wavelengths of light.
The R1-R6 photoreceptors that mediate motion vision go through a very precise sorting process to connect each axon to the correct target cell. We have found that the immunoglobulin family protein Sidekick plays an essential adhesive role to form a stable scaffold that allows these axons to find their targets (Astigarraga et al., 2018). In epithelia, Sidekick is localized to contacts between three or more cells, and is necessary for normal cell rearrangements. We have shown that it is the first described component of tricellular adherens junctions, and that it interacts with ZO-1 and Afadin homologues to tether actin filament ends and resist tension on these cell contacts during epithelial remodeling (Letizia et al., 2019) .

Another interesting question is how synapses grow to reach the correct size during development. We are using the neuromuscular junction as a model to understand how synapse growth is coordinated with growth of the target muscles. We have found that Insulin receptor pathway signaling locally affects the extent of postsynaptic differentiation, which is sensed by motor neurons to control the elaboration of presynaptic structures. A specific isoform of the guanine nucleotide exchange factor Pix is an important mediator of this process (Ho et al., in preparation). We would like to understand how Insulin signaling regulates Pix, how Pix promotes postsynaptic differentiation, and what molecule conveys information about postsynaptic differentiation to the motor neuron.