Francesco Lotti

Publications (2)38.46 Total impact

• Article: An SMN-Dependent U12 Splicing Event Essential for Motor Circuit Function.

  Francesco Lotti, Wendy L Imlach, Luciano Saieva, Erin S Beck, Le T Hao, Darrick K Li, Wei Jiao, George Z Mentis, Christine E Beattie, Brian D McCabe, Livio Pellizzoni
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  ABSTRACT: Spinal muscular atrophy (SMA) is a motor neuron disease caused by deficiency of the ubiquitous survival motor neuron (SMN) protein. To define the mechanisms of selective neuronal dysfunction in SMA, we investigated the role of SMN-dependent U12 splicing events in the regulation of motor circuit activity. We show that SMN deficiency perturbs splicing and decreases the expression of a subset of U12 intron-containing genes in mammalian cells and Drosophila larvae. Analysis of these SMN target genes identifies Stasimon as a protein required for motor circuit function. Restoration of Stasimon expression in the motor circuit corrects defects in neuromuscular junction transmission and muscle growth in Drosophila SMN mutants and aberrant motor neuron development in SMN-deficient zebrafish. These findings directly link defective splicing of critical neuronal genes induced by SMN deficiency to motor circuit dysfunction, establishing a molecular framework for the selective pathology of SMA.
  Cell 10/2012; 151(2):440-54. · 32.40 Impact Factor
• Article: A role for SMN exon 7 splicing in the selective vulnerability of motor neurons in spinal muscular atrophy.

  Matteo Ruggiu, Vicki L McGovern, Francesco Lotti, Luciano Saieva, Darrick K Li, Shingo Kariya, Umrao R Monani, Arthur H M Burghes, Livio Pellizzoni
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  ABSTRACT: Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by homozygous loss of the Survival Motor Neuron 1 (SMN1) gene. In the absence of SMN1, inefficient inclusion of exon 7 in transcripts from the nearly identical SMN2 gene results in ubiquitous SMN decrease but selective motor neuron degeneration. Here we investigated whether cell type-specific differences in the efficiency of exon 7 splicing contribute to the vulnerability of SMA motor neurons. We show that normal motor neurons express markedly lower levels of full-length SMN mRNA from SMN2 than do other cells in the spinal cord. This is due to inefficient exon 7 splicing that is intrinsic to motor neurons under normal conditions. We also find that SMN depletion in mammalian cells decreases exon 7 inclusion through a negative feedback loop affecting the splicing of its own mRNA. This mechanism is active in vivo and further decreases the efficiency of exon 7 inclusion specifically in motor neurons of severe-SMA mice. Consistent with expression of lower levels of full-length SMN, we find that SMN-dependent downstream molecular defects are exacerbated in SMA motor neurons. These findings suggest a mechanism to explain the selective vulnerability of motor neurons to loss of SMN1.
  Molecular and cellular biology 01/2012; 32(1):126-38. · 6.06 Impact Factor