Different types of motor neuron vary in their sensitivity to neurodegeneration in amyotrophic lateral sclerosis, with the neurons innervating the lateral motor column among the most susceptible. What sets them apart from less sensitive neurons? They highly express a particular cluster of microRNAs, according to a paper in the May 21 Cell Reports online. The authors, from the Academia Sinica in Taipei, Taiwan, discovered the miR17~92 cluster blocks apoptosis. If this cluster malfunctions, it might leave the lateral motor column neurons vulnerable, the authors suggest.
Senior author Jun-An Chen had previously found that lateral motor column (LMC) motor neurons wither in mouse embryos without the miRNA processor Dicer (Chen and Wichterle, 2012). The neurons must require microRNAs to survive, but which ones? Joint first authors Ying-Tsen Tung and Ya-Lin Lu used RNA sequencing to look for specific microRNAs highly expressed in the LMC motor neurons. They found a set of six known collectively as miR-17~92. The members of this microRNA cluster are all encoded and transcribed together on chromosome 13, but act individually (reviewed in Mogilyansky and Rigoutsos, 2013). Deleting miR-17~92 in embryos resulted in degeneration of the limb-innervating neurons (see image above).
To identify the genes silenced by the miR-17~92 cluster, the authors analyzed the transcriptomes of neurons from the knockout embryos. One obvious candidate leapt out. Phosphatase and tensin homolog (PTEN) is a known miR-17~92 target and mediator of apoptosis in neural progenitor cells and in certain cancers (Liu et al., 2013; Nakanishi et al., 2014). PTEN was upregulated in the knockout neurons, and blocking or deleting it in the miR-17~92 knockout embryos rescued the motor neuron apoptosis. Conversely, overexpressing miR-17~92 resulted in embryos with less PTEN, and more motor neurons, suggesting the cluster prevented programmed cell death.
The authors suggest that the miR-17~92/PTEN pathway may underlie the sensitivity of LMC neurons to ALS. Chen speculated that aging or cellular stressors could alter the levels of the cluster members, and the neurons’ defenses. However, he said he has not yet directly linked miR-17~92 to motor neuron disease.
Yeliz Aydemir of the University of Massachusetts Medical School in Worcester, who was not involved in the study, praised the research but cautioned that the ALS link is tenuous for now. “We do not know about the expression of this microRNA cluster in adult motor neurons, and whether it has this survival role in adult motor neurons,” she pointed out. In follow-up experiments, Chen and colleagues plan to investigate the role of miR-17~92 in the adult neurons of ALS mouse models and in patient cells, as well as to understand what PTEN does in the nucleus.—Amber Dance
- Chen JA, Wichterle H. Apoptosis of limb innervating motor neurons and erosion of motor pool identity upon lineage specific dicer inactivation. Front Neurosci. 2012;6:69. Epub 2012 May 17 PubMed.
- Mogilyansky E, Rigoutsos I. The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ. 2013 Dec;20(12):1603-14. PubMed.
- Liu XS, Chopp M, Wang XL, Zhang L, Hozeska-Solgot A, Tang T, Kassis H, Zhang RL, Chen C, Xu J, Zhang ZG. MicroRNA-17-92 cluster mediates the proliferation and survival of neural progenitor cells after stroke. J Biol Chem. 2013 May 3;288(18):12478-88. Epub 2013 Mar 19 PubMed.
- Nakanishi A, Kitagishi Y, Ogura Y, Matsuda S. The tumor suppressor PTEN interacts with p53 in hereditary cancer (Review). Int J Oncol. 2014 Jun;44(6):1813-9. Epub 2014 Apr 10 PubMed.
- Marcuzzo S, Kapetis D, Mantegazza R, Baggi F, Bonanno S, Barzago C, Cavalcante P, Kerlero de Rosbo N, Bernasconi P. Altered miRNA expression is associated with neuronal fate in G93A-SOD1 ependymal stem progenitor cells. Exp Neurol. 2014 Mar;253:91-101. Epub 2013 Dec 21 PubMed.
- Yang DJ, Wang XL, Ismail A, Ashman CJ, Valori CF, Wang G, Gao S, Higginbottom A, Ince PG, Azzouz M, Xu J, Shaw PJ, Ning K. PTEN regulates AMPA receptor-mediated cell viability in iPS-derived motor neurons. Cell Death Dis. 2014 Feb 27;5:e1096. PubMed.
- Kirby J, Ning K, Ferraiuolo L, Heath PR, Ismail A, Kuo SW, Valori CF, Cox L, Sharrack B, Wharton SB, Ince PG, Shaw PJ, Azzouz M. Phosphatase and tensin homologue/protein kinase B pathway linked to motor neuron survival in human superoxide dismutase 1-related amyotrophic lateral sclerosis. Brain. 2011 Feb;134(Pt 2):506-17. PubMed.
- Tung YT, Lu YL, Peng KC, Yen YP, Chang M, Li J, Jung H, Thams S, Huang YP, Hung JH, Chen JA. Mir-17∼92 Governs Motor Neuron Subtype Survival by Mediating Nuclear PTEN. Cell Rep. 2015 May 20; PubMed.