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

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∼92 cluster is enriched in embryonic stem cell (ESC)-derived LMC-MNs and that conditional mir-17∼92 deletion in MNs results in the death of LMC-MNs in vitro and in vivo. mir-17∼92 overexpression rescues MNs from apoptosis, which occurs spontaneously during embryonic development. PTEN is a primary target of mir-17∼92 responsible for LMC-MN degeneration. Additionally, mir-17∼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. [Display omitted] •The survival of limb-innervating motor neurons depends upon the mir-17∼92 cluster•mir-17∼92 targets PTEN and E3 ubiquitin ligases to regulate PTEN expression•miRNA couples post-transcriptional regulation and post-translational modification•This coupling regulates the subcellular localization of target proteins Tung et al. show that PTEN is a primary target of mir-17∼92 and is responsible for limb-innervating motor neuron degeneration. mir-17∼92 directly targets components of E3 ubiquitin ligases, affecting PTEN subcellular localization through monoubiquitination and providing limb-innervating motor neurons with an intricate defensive mechanism that controls their survival.