TY - JOUR T1 - Neural Cadherin Plays Distinct Roles for Neuronal Survival and Axon Growth under Different Regenerative Conditions JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0325-20.2020 SP - ENEURO.0325-20.2020 AU - Márcio Ribeiro AU - Konstantin Levay AU - Benito Yon AU - Ana Ayupe AU - Yadira Salgueiro AU - Kevin K. Park Y1 - 2020/09/23 UR - http://www.eneuro.org/content/early/2020/09/23/ENEURO.0325-20.2020.abstract N2 - Growing axons in the central nervous system (CNS) often migrate along specific pathways to reach their targets. During embryonic development, this migration is guided by different types of cell adhesion molecules (CAMs) present on the surface of glial cells or other neurons, including the neural cadherin (NCAD). Axons in the adult CNS can be stimulated to regenerate, and travel long distances. Crucially, however, while a few axons are guided effectively through the injured nerve under certain conditions, most axons never migrate properly. The molecular underpinnings of the variable growth, and the glial CAMs that are responsible for CNS axon regeneration remain unclear. Here we used optic nerve crush to demonstrate that NCAD plays multifaceted functions in facilitating CNS axon regeneration. Astrocyte-specific deletion of NCAD dramatically decreases regeneration induced by PTEN ablation in retinal ganglion cells (RGCs). Consistent with NCAD’s tendency to act as homodimers, deletion of NCAD in RGCs also reduces regeneration. Deletion of NCAD in astrocytes neither alters RGCs’ mTORC1 activity nor lesion size, two factors known to affect regeneration. Unexpectedly however, we find that NCAD deletion in RGCs reduces PTEN-deletion induced RGC survival. We further show that NCAD deletion, in either astrocytes or RGCs, has negligible effects on the regeneration induced by ciliary neurotrophic factor (CNTF), suggesting that other CAMs are critical under this regenerative condition. Consistent with this notion, CNTF induces expression various integrins known to mediate cell adhesion. Together, our study reveals multilayered functions of NCAD and a molecular basis of variability in guided axon growth.Significance Statement Growing axons often travel long distances and migrate along explicit pathways to reach their targets. Cell adhesion molecules (CAMs) including cadherins play vital roles in these processes during development. However, it remains unclear whether the same factors are involved for the adult axons after injury. This study used knockout mice to demonstrate that ablation of NCAD in astrocytes or retinal ganglion cells, prevents regeneration and cell survival induced by PTEN deletion. In contrary, NCAD deletion has negligible effects on the regeneration and survival induced by cytokines, suggesting that distinct CAMs control axon adhesion and growth under different regenerative conditions. Together, our study illustrates cadherins’ versatile functions in the injured CNS, and points to distinct mechanisms that shape directed axon growth. ER -