Mir-17 similar to 92 Governs Motor Neuron Subtype Survival by Mediating Nuclear PTEN

Abstract

Motor neurons (MNs) are unique because they project their axons outside of the CNS to innervate the peripheral muscles. Limb-innervating lateral motor column MNs (LMC-MNs) travel substantially to innervate distal limb mesenchyme. How LMC-MNs fine-tune the balance between survival and apoptosis while wiring the sensorimotor circuit en route remains unclear. Here, we show that the mir-17 similar to 92 cluster is enriched in embryonic stem cell (ESC)derived LMC-MNs and that conditional mir-17 similar to 92 deletion in MNs results in the death of LMC-MNs in vitro and in vivo. mir-17 similar to 92 overexpression rescues MNs from apoptosis, which occurs spontaneously during embryonic development. PTEN is a primary target of mir-17 similar to 92 responsible for LMC-MN degeneration. Additionally, mir-17 similar to 92 directly targets components of E3 ubiquitin ligases, affecting PTEN subcellular localization through monoubiquitination. This miRNA-mediated regulation modulates both target expression and target subcellular localization, providing LMC-MNs with an intricate defensive mechanism that controls their survival.