The Cbln family of proteins interact with multiple signaling pathways

• Published in: Journal of neurochemistry 2012-06, Vol.121 (5), p.717-729
• Main Authors: Wei, Peng, Pattarini, Roberto, Rong, Yongqi, Guo, Hong, Bansal, Parmil K, Kusnoor, Sheila V, Deutch, Ariel Y, Parris, Jennifer, Morgan, James I
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Brain; Brain - metabolism; Cbln1; Cbln4; Cell physiology; Cerebellum; DCC; DCC protein; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Medical sciences; Mice; Mice, Knockout; Molecular and cellular biology; Neostriatum; Nerve Tissue Proteins - metabolism; netrin; neurexin; Neurochemistry; Neurons; Protein Precursors - metabolism; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Signal transduction; Signal Transduction - physiology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Synapses; Tumors
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2012.07648.x

J. Neurochem. (2012) 121, 717–729. Cerebellin precursor protein (Cbln1) is essential for synapse integrity in cerebellum through assembly into complexes that bridge pre‐synaptic β‐neurexins (Nrxn) to post‐synaptic GluRδ2. However, GluRδ2 is largely cerebellum‐specific, yet Cbln1 and its little studied family members, Cbln2 and Cbln4, are expressed throughout brain. Therefore, we investigated whether additional proteins mediate Cbln family actions. Whereas Cbln1 and Cbln2 bound to GluRδ2 and Nrxns1‐3, Cbln4 bound weakly or not at all, suggesting it has distinct binding partners. In a candidate receptor‐screening assay, Cbln4 (but not Cbln1 or Cbln2) bound selectively to the netrin receptor, (deleted in colorectal cancer (DCC) in a netrin‐displaceable fashion. To determine whether Cbln4 had a netrin‐like function, Cbln4‐null mice were generated. Cbln4‐null mice did not phenocopy netrin‐null mice. Cbln1 and Cbln4 were likely co‐localized in neurons thought to be responsible for synaptic changes in striatum of Cbln1‐null mice. Furthermore, complexes containing Cbln1 and Cbln4 had greatly reduced affinity to DCC but increased affinity to Nrxns, suggesting a functional interaction. However, Cbln4‐null mice lacked the striatal synaptic changes seen in Cbln null mice. Thus, Cbln family members interact with multiple receptors/signaling pathways in a subunit composition‐dependent manner and have independent functions with Cbln4 potentially involved in the less well‐characterized role of netrin/DCC in adult brain. Cbln1 binds to neurexins and GluRδ2 on pre‐ and post‐synaptic membranes, respectively to stabilize synapses. We show that another family member, Cbln4 binds weakly or not at all to these receptors and cbln4‐null mice lack the synaptic defects seen in cbln1‐knockout mice. However, Cbln4 binds uniquely to DCC in a netrin‐displaceable manner suggesting it functions via this receptor in brain.