analysis of the fibroblast growth factor system reveals alterations in a mouse model of spinal muscular atrophy纤维母细胞生长因子系统的分析揭示了改变脊髓性肌肉萎缩症的小鼠模型.pdfVIP

Analysis of the Fibroblast Growth Factor System Reveals Alterations in a Mouse Model of Spinal Muscular Atrophy 1,2 1 1 3 1,2 Niko Hensel , Andreas Ratzka , Hella Brinkmann , Lars Klimaschewski , Claudia Grothe , Peter Claus1,2* 1 Institute of Neuroanatomy, Hannover Medical School, Hannover, Germany, 2 Center for Systems Neuroscience, Hannover, Germany, 3 Division of Neuroanatomy, Innsbruck Medical University, Innsbruck, Austria Abstract The monogenetic disease Spinal Muscular Atrophy (SMA) is characterized by a progressive loss of motoneurons leading to muscle weakness and atrophy due to severe reduction of the Survival of Motoneuron (SMN) protein. Several models of SMA show deficits in neurite outgrowth and maintenance of neuromuscular junction (NMJ) structure. Survival of motoneurons, axonal outgrowth and formation of NMJ is controlled by neurotrophic factors such as the Fibroblast Growth Factor (FGF) system. Besides their classical role as extracellular ligands, some FGFs exert also intracellular functions controlling neuronal differentiation. We have previously shown that intracellular FGF-2 binds to SMN and regulates the number of a subtype of nuclear bodies which are reduced in SMA patients. In the light of these findings, we systematically analyzed the FGF-system comprising five canonical receptors and 22 ligands in a severe mouse model of SMA. In this study, we demonstrate widespread alterations of the FGF-system in both muscle and spinal cord. Importantly, FGF-receptor 1 is upregulated in spinal cord at a pre-symptomatic stage as well as in a mouse motoneuron-like cell-line NSC34 based model of SMA. Consistent with that, phosphorylation