The disease myotonic dystrophy is mainly known for how it wastes away its sufferers’ muscles, but it also attacks the nervous system. As described in the April 8 Cell Stem Cell, researchers in France used stem cells from human embryos diagnosed with myotonic dystrophy type 1 (DM1) to investigate these nerve cell effects. They discovered that DM1 cells lack normal amounts of proteins in the SLITRK family, which regulate neurite outgrowth and synapse formation (Aruga and Mikoshiba, 2003). Although exactly how the SLITRK defect arises remains unknown, the embryonic stem (ES) cell-derived DM1 cells could provide a useful system to screen for therapies, said Tom Cooper of the Baylor College of Medicine in Houston, Texas, who was not involved in the study.

Beyond myotonia—a condition marked by difficulty relaxing muscles—people with DM1 suffer central nervous system (CNS) symptoms. They are excessively sleepy and have cognitive impairment or mental retardation (de León and Cisneros, 2008). Pathologically, the disease causes motor neuron axonopathy (Krishnan and Kiernan, 2006). Motor neuron axons, of course, are also affected in amyotrophic lateral sclerosis (ALS), another disease that has a lesser-known cognitive component, as well.

Not just the axonopathy, but also the cellular pathology of DM1 brings to mind ALS. “DM was the founding member of a family of diseases which seem to be caused by toxic RNAs,” said Maurice Swanson of the University of Florida in Gainesville, who was not part of the current research. RNA splicing alterations have become a hot area of ALS research (see ARF related news story on Kwiatkowski et al., 2009 and Vance et al., 2009). DM1 is caused by expansion of a CTG triplet in the 3’-untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene. The extended DMPK RNAs build up in the nucleus, where they form inclusion bodies and sequester splicing factors. This alters expression of a number of genes, including the NMDA receptor 1 and tau (Jiang et al., 2004; Sergeant et al., 2001). Scientists presume all these altered RNAs cause DM1’s pleiotropic pathology.

To simplify studies of pleiotrophic diseases, many researchers are turning to stem cell-based models created from the tissue of affected people (see ARF related news story). “The ability to take ES cells and do [gene expression studies]—to me, that is the main take-home message” from the study, Cooper said. To that end, first author Antoine Marteyn and senior author Cécile Martinat, of the Institute for Stem Cell Therapy in Evry, France, started with DM1-positive embryonic stem cell lines (Mateizel et al., 2006). They differentiated the ES cells, as well as wild-type control lines, into neural precursor cells. Using whole-gene expression profiling, they discovered that 8 genes were downregulated, and 7 upregulated, in the DM1 cells.

Of those genes, Marteyn and colleagues focused further studies on the gene SLITRK4. The researchers differentiated the ES lines further into motor neurons so they could examine not only the neural phenotype but also the formation of neuromuscular junctions. The DM1 cells exhibited greater neurite outgrowth, with longer projections and more microtubule associated protein 2-positive staining, than control cells. But when co-cultured with myoblasts to model synapse formation, the neurons produced only 10-20 percent of the number of neuromuscular contacts the controls had.

The researchers checked other members of the SLITRK family and found SLITRK4 expression, too, was reduced in their DM1 model. These genes subsequently turned out to be less expressed in brain tissue samples from fetuses and adults with DM1, as well.

“The idea that there is abnormal neurogenesis in DM1 is very novel,” Swanson said. Moreover, although DM1 can be adult-onset, the study suggests that neurogenesis and synaptogenesis are defective during development. “The seeds of destruction are planted early,” Swanson said. Similarly, he noted, triplet repeats can cause a late-onset disease, Fragile X tremor/ataxia syndrome, that is related to early onset fragile X syndrome, another disease of toxic RNAs (see ARF related news story on Jin et al., 2007 and Sofola et al., 2007).

Tantalizingly, the neurogenesis defect is amenable to repair, the scientists found. They transfected their cell cultures with SLITRK constructs, and found their overexpression returned neurite outgrowth to normal. Thus, the study suggests the future possibility of targeting the neural defect in people with DM1, wrote Ben Cheah—a graduate student in the laboratory of Matthew Kiernan at the University of New South Wales in Sydney, Australia—in an e-mail to ARF. He suggested that such a treatment might not require altering neuron biology; doctors might be able to protect neuromuscular junctions by exposing the muscles to the SLITRK proteins.

Before planning targeted therapies, scientists still have much to do to understand how the mutant dystrophia myotonica kinase affects SLITRK in neurons and other genes in other cell types, Cooper said. However, he suggested that a cell line such as Marteyn’s, with a clear DM1 phenotype that can be rescued, might be useful in screening small molecules or RNAs in a search for treatments.—Amber Dance


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News Citations

  1. New Gene for ALS: RNA Regulation May Be Common Culprit
  2. Hereditary Diseases: A Natural Fit For iPSC Modeling
  3. One Gene, Two Diseases: The Long and Short of Fragile X

Paper Citations

  1. . Identification and characterization of Slitrk, a novel neuronal transmembrane protein family controlling neurite outgrowth. Mol Cell Neurosci. 2003 Sep;24(1):117-29. PubMed.
  2. . Myotonic dystrophy 1 in the nervous system: from the clinic to molecular mechanisms. J Neurosci Res. 2008 Jan;86(1):18-26. PubMed.
  3. . Axonal function and activity-dependent excitability changes in myotonic dystrophy. Muscle Nerve. 2006 May;33(5):627-36. PubMed.
  4. . Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009 Feb 27;323(5918):1205-8. PubMed.
  5. . Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009 Feb 27;323(5918):1208-11. PubMed.
  6. . Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum Mol Genet. 2004 Dec 15;13(24):3079-88. PubMed.
  7. . Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. Hum Mol Genet. 2001 Sep 15;10(19):2143-55. PubMed.
  8. . Derivation of human embryonic stem cell lines from embryos obtained after IVF and after PGD for monogenic disorders. Hum Reprod. 2006 Feb;21(2):503-11. PubMed.
  9. . Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome. Neuron. 2007 Aug 16;55(4):556-64. PubMed.
  10. . RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. Neuron. 2007 Aug 16;55(4):565-71. PubMed.

Further Reading


  1. . Neuropathology does not Correlate with Regional Differences in the Extent of Expansion of CTG Repeats in the Brain with Myotonic Dystrophy Type 1. Acta Histochem Cytochem. 2010 Dec 29;43(6):149-56. PubMed.
  2. . RNA in brain disease: no longer just "the messenger in the middle". J Neuropathol Exp Neurol. 2007 Jun;66(6):461-8. PubMed.
  3. . RNA-mediated neuromuscular disorders. Annu Rev Neurosci. 2006;29:259-77. PubMed.
  4. . Mis-splicing of Tau exon 10 in myotonic dystrophy type 1 is reproduced by overexpression of CELF2 but not by MBNL1 silencing. Biochim Biophys Acta. 2011 Jul;1812(7):732-42. PubMed.
  5. . Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy. Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13915-20. PubMed.
  6. . Altered splicing of Tau in DM1 is different from the foetal splicing process. FEBS Lett. 2009 Feb 18;583(4):675-9. PubMed.
  7. . Myotonic dystrophy transgenic mice exhibit pathologic abnormalities in diaphragm neuromuscular junctions and phrenic nerves. J Neuropathol Exp Neurol. 2008 Aug;67(8):763-72. PubMed.

Primary Papers

  1. . Mutant human embryonic stem cells reveal neurite and synapse formation defects in type 1 myotonic dystrophy. Cell Stem Cell. 2011 Apr 8;8(4):434-44. PubMed.