Contactin-4 Mediates Axon-Target Specificity and Functional Development of the Accessory Optic System

Abstract

SUMMARY The mammalian eye-to-brain pathway includes more than twenty parallel circuits, each consisting of precise long-range connections between specific sets of retinal ganglion cells (RGCs) and target structures in the brain. The mechanisms that drive assembly of these parallel connections, and the functional implications of their specificity remain unresolved. Here we show that in absence of contactin 4 (CNTN4) or one of its binding partners, amyloid precursor protein (APP), a subset of direction selective retinal ganglion cells fail to target the nucleus of the optic tract (NOT) - the accessory optic system (AOS) target controlling horizontal image stabilization. Conversely, ectopic expression of CNTN4 biases RGCs to arborize in the NOT, and that process also requires APP. Our data reveal critical and novel roles for CNTN4/APP in promoting target-specific axon arborization and they highlight the importance of this process for functional development of a behaviorally-relevant parallel visual pathway.

Association of Cell Adhesion Molecules Contactin-6 and Latrophilin-1 Regulates Neuronal Apoptosis

“…Cntn4 and Cntn5 also appear to be engaged in cis- and trans- interactions with their homologs or with other proteins (Traka et al, 2003; Cui et al, 2004; Osterfield et al, 2008; Ye et al, 2008, 2011; Bouyain and Watkins, 2010; Shimoda et al, 2012; Yamagata and Sanes, 2012; Ashrafi et al, 2014; Osterhout et al, 2015). Cntn6 is known to complex with other membrane proteins as well, including Ptpra, Ptprg, PTPσ, Notch, and Chl1 (Cui et al, 2004; Hu et al, 2006; Ye et al, 2008; Bouyain and Watkins, 2010; Zuko et al, 2011; Huang et al, 2016) Thus, interaction with other protein partners appears as a common theme in the mode of action of contactins.…”

Structural Basis for Interactions Between Contactin Family Members and Protein-tyrosine Phosphatase Receptor Type G in Neural Tissues

“…Such a possibility would be consistent with our results showing that PTPRG binds to CNTN3-6 in essentially identical fashion. These PTPRG⅐CNTN co-receptors might associate with known CNTN-binding partners, such as L1 family members, CNTNAPs, or amyloid precursor proteins (8,11,32,34,35). Targets of PTPRG⅐CNTN co-receptor complexes might also include yet to be identified proteins that have weak affinities for either PTPRG or a given CNTN but would associate with a PTPRG⅐CNTN co-receptor complex to form a holoreceptor in much the same way that semaphorins, neuropilins, and plexins do (36).…”

“…For example, CNTN3-5 are expressed in neuronal layers of chick embryo retinas (10). Furthermore, CNTN4 is expressed by axons of specific retinal ganglion cells to target the accessory optic system (11). It is also found on olfactory sensory neurons and guides their axons to specific glomeruli of the olfactory bulb, thus playing a role in odor map formation (12).…”

Ipsilateral and Contralateral Retinal Ganglion Cells Express Distinct Genes during Decussation at the Optic Chiasm

“…The vertebrate retina, with its three cellular layers and six neuronal classes, has been a useful model for studying general principles of neurogenesis and axon guidance. Each class of retinal cells can be further divided into morphologically and functionally distinct subtypes, and recent efforts have identified the molecular programs that establish these differences within neuronal classes, such as amacrine, bipolar, and retinal ganglion cell (RGC) subtypes (Kim et al, 2008; Badea et al, 2009; Kay et al, 2011a, 2011b; Watson et al, 2012; Jiang et al, 2013; Sajgo et al, 2014; Macosko et al, 2015; Osterhout et al, 2015; Sanes and Masland, 2015; Tang et al, 2015; Jin et al, 2015; Rousso et al, 2016; Shekhar et al, 2016). RGCs, as the only projection neurons of the retina, can be additionally distinguished by the laterality of their axonal projection to targets in the thalamus and midbrain.…”