Person:

Krishnaswamy, Arjun

Mutations in the gene encoding the immunoglobulin-superfamily member cell adhesion molecule contactin1 (CNTN1) cause lethal congenital myopathy in human patients and neurodevelopmental phenotypes in knockout mice. Whether the mutant mice provide an accurate model of the human disease is unclear; resolving this will require additional functional tests of the neuromuscular system and examination of Cntn1 mutations on different genetic backgrounds that may influence the phenotype. Toward these ends, we have analyzed a new, spontaneous mutation in the mouse Cntn1 gene that arose in a BALB/c genetic background. The overt phenotype is very similar to the knockout of Cntn1, with affected animals having reduced body weight, a failure to thrive, locomotor abnormalities, and a lifespan of 2–3 weeks. Mice homozygous for the new allele have CNTN1 protein undetectable by western blotting, suggesting that it is a null or very severe hypomorph. In an analysis of neuromuscular function, neuromuscular junctions had normal morphology, consistent with previous studies in knockout mice, and the muscles were able to generate appropriate force when normalized for their reduced size in late stage animals. Therefore, the Cntn1 mutant mice do not show evidence for a myopathy, but instead the phenotype is likely to be caused by dysfunction in the nervous system. Given the similarity of CNTN1 to other Ig-superfamily proteins such as DSCAMs, we also characterized the expression and localization of Cntn1 in the retinas of mutant mice for developmental defects. Despite widespread expression, no anomalies in retinal anatomy were detected histologically or using a battery of cell-type specific antibodies. We therefore conclude that the phenotype of the Cntn1 mice arises from dysfunction in the brain, spinal cord or peripheral nervous system, and is similar in either a BALB/c or B6;129;Black Swiss background, raising a possible discordance between the mouse and human phenotypes resulting from Cntn1 mutations.

In the mammalian retina, processes of ~70 types of interneurons form specific synapses on ~30 types of retinal ganglion cells (RGCs) in a neuropil called the inner plexiform layer (IPL). Each RGC type extracts salient features from visual input, which are sent deeper into the brain for further processing 1-4. The specificity and stereotypy of synapses formed in the IPL account for the feature-detecting ability of the RGCs. Here, we analyze the development and function of synapses on one RGC type, the W3B-RGC5,6. These cells have the remarkable property of responding when the timing of a small object's movement differs from that of the background, but not when they coincide6. Such cells, called “local edge detectors” or “object motion sensors”, can distinguish moving objects from a visual scene that is also moving6-12. We show that W3B-RGCs receive strong and selective input from an unusual excitatory amacrine cell type called VG3-AC. Both W3B-RGCs and VG3-ACs express the immunoglobulin superfamily recognition molecule Sidekick-2 (Sdk2)13,14, and both loss- and gain-of function studies indicate that Sdk2-dependent homophilic interactions are necessary for the selectivity of the connection. The Sdk2-specified synapse is essential for visual responses of W3B-RGCs: whereas bipolar cells relay visual input directly to most RGCs, the W3B-RGCs receive much of their input indirectly, via the VG3-ACs. This non-canonical circuit introduces a delay into the pathway from photoreceptors in the center of the receptive field to W3B-RGCs, which could improve their ability to judge the synchrony of local and global motion.