Innervation under microRNA control

Sci. Signal.  02 Jun 2015:
Vol. 8, Issue 379, pp. ec143
DOI: 10.1126/scisignal.aac6692

Motor neurons project from within the central nervous system (such as the spinal cord) to innervate muscles and control movement. MicroRNA (miRNA) biogenesis is critical to the survival of motor neurons during development. Tung et al. found that miR-17-92, a miRNA cluster that inhibits apoptosis, was enriched in limb-innervating lateral motor column motor neurons (LMC-MNs) in the spinal cords of mouse embryos. Although many embryos in which miR-17-92 was deleted selectively from motor neurons died pre- or perinatally, the surviving pups had a decreased number of LMC-MNs and exhibited movement defects. Compared with those from controls, spinal cord sections from global miR17-92–knockout mouse embryos had an increased number of LMC-MNs that stained positive for an apoptotic marker. Axons that projected to limb muscles in the knockout embryos were present in thinner bundles and had arborization defects compared with those in the control embryos. In cocultures of control and miR-17-92–knockout embryonic stem cells engineered to express red or green fluorescent protein, respectively, and differentiate into motor neurons, only the knockout cells underwent apoptosis. Microarray analysis of primary spinal cord motor neurons from wild-type and miR-17-92–knockout embryos revealed 15 candidate targets involved in apoptosis; the transcript encoding the phosphatase PTEN was among the top of these. Monoubiquitylation promotes the nuclear translocation of PTENs. Compared with motor neurons in wild-type embryos, those in the knockout embryos had increased abundance of total, nuclear and monoubiquitylated PTEN. Luciferase assays using wild-type and mutant 3ʹ-untranslated regions confirmed that transcripts encoding PTEN and several E3 ubiquitin ligases were direct targets of miR-17-92. Mice in which both PTEN and miR-17-92 were knocked out exhibited enhanced survival of motor neurons. The addition of a peptide that prevented PTEN monoubiquitylation suppressed apoptosis of motor neurons cultured from the miR-17-92–knockout mice. The findings suggest that the miR-17-92 cluster promotes the survival of limb-innervating motor neurons by suppressing PTEN production and PTEN nuclear localization.

Y.-T. Tung, Y.-L. Lu, K.-C. Peng, Y.-P. Yen, M. Chang, J. Li, H. Jung, S. Thams, Y.-P. Huang, J.-H. Hung, J.-A. Chen, Mir-17~92 governs motor neuron subtype survival by mediating nuclear PTEN. Cell Reports 11, 1–14 (2015). [PubMed]