CADM3, also known as Necl-1, is a neuronal specific adhesion molecule. It plays a crucial role in mediating direct contact and interaction between axons and glia, with axonal CADM3 binding to glial CADM4. This interaction is essential for the structural organization of myelinated fibers in the peripheral nerve. CADM3 may also be involved in regulating cone synapse formation in the mouse retina and could be associated with pathways like cAMP/PKA signaling in colon cancer [1,2,3,4]. Genetic models, such as mouse models, are valuable for studying its functions [3].

In mice, Cadm3 knockout or mutations have provided insights into its functions. In Cadm3 null mice, axonal organization abnormalities were observed, similar to those in Cadm4 null mice, indicating Cadm3 as the main axonal ligand for glial Cadm4 [3]. Cadm3Y170C mice, carrying a corresponding human mutation, showed abnormal axonal organization, despite normal nerve conduction and myelin morphology [2]. In vitro studies with Cadm3 knockdown or over-expression in neurons also suggest that Cadm3 may act as a negative regulator of PNS myelination, potentially through interfering with the activation of the pro-myelinating PI3K/Akt pathway [5].

In conclusion, CADM3 is essential for axon-glia interactions and myelination in the peripheral nervous system, as well as for cone synapse formation in the retina. Studies using gene knockout or mutant mouse models have been instrumental in revealing its role in these processes and in understanding the disease mechanisms related to Charcot-Marie-Tooth disease [1,2,3,5].

References:

1. Kawashima, Rumi, Matsushita, Kenji, Mandai, Kenji, Nishida, Kohji, Takai, Yoshimi. 2024. Necl-1/CADM3 regulates cone synapse formation in the mouse retina. In iScience, 27, 109577. doi:10.1016/j.isci.2024.109577. https://pubmed.ncbi.nlm.nih.gov/38623325/

2. Rebelo, Adriana P, Cortese, Andrea, Abraham, Amit, Shy, Michael E, Zuchner, Stephan. . A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement. In Brain : a journal of neurology, 144, 1197-1213. doi:10.1093/brain/awab019. https://pubmed.ncbi.nlm.nih.gov/33889941/

3. Sukhanov, Natasha, Vainshtein, Anya, Eshed-Eisenbach, Yael, Peles, Elior. 2021. Differential Contribution of Cadm1-Cadm3 Cell Adhesion Molecules to Peripheral Myelinated Axons. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 41, 1393-1400. doi:10.1523/JNEUROSCI.2736-20.2020. https://pubmed.ncbi.nlm.nih.gov/33397712/

4. Xie, Zhengyong, Ke, Yongli, Li, Zehang, Ding, Hongliang, Cheng, Liyang. 2023. GRIK5 stimulates colon cancer growth and metastasis through cAMP/PKA/CADM3 signaling. In Cell biology international, 47, 1259-1266. doi:10.1002/cbin.12022. https://pubmed.ncbi.nlm.nih.gov/36959746/

5. Chen, Ming-Shuo, Kim, Hyosung, Jagot-Lacoussiere, Léonard, Maurel, Patrice. 2016. Cadm3 (Necl-1) interferes with the activation of the PI3 kinase/Akt signaling cascade and inhibits Schwann cell myelination in vitro. In Glia, 64, 2247-2262. doi:10.1002/glia.23072. https://pubmed.ncbi.nlm.nih.gov/27658374/