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Motor neurons (MNs) are unique because they project their axons outside of the central nervous system 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-derived LMC-MNs, and that the conditional mir-17~92 deletion in MNs resulted in the death of LMC-MNs in vitro and in vivo.mir-17~92 overexpression rescued MNs from apoptosis, which occurs spontaneously during embryonic development.Pten was identified as a primary target of mir-17~92 responsible for LMC-MN degeneration.Additionally, mir-17~92 directly targeted components of E3 ubiquitin ligases, affecting Pten subcellular localization through monoubiquitination.The regulation of miRNA that regulates target expression and target subcellular localization provides LMC-MNs with an intricate defensive mechanism that controls their survival.