Neural Cadherin Plays Distinct Roles for Neuronal Survival and Axon Growth under Different Regenerative Conditions

Márcio Ribeiro, Konstantin Levay, Benito Yon, Ana C. Ayupe, Yadira Salgueiro, Kevin K. Park
2020 eNeuro  
Growing axons in the 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
more » ... r 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 phosphatase and tensin homolog (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' mammalian target of rapamycin complex 1 (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. 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 knock-out (KO) mice to demonstrate that ablation of NCAD in astrocytes or retinal ganglion cells (RGCs), prevents regeneration and cell survival induced by phosphatase and tensin homolog (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.
doi:10.1523/eneuro.0325-20.2020 fatcat:uiviqjxn3fcrhkcugutsptsbhq