Myelin is a crucial component of vertebrate nervous systems. Both regenerative therapies and treatment of demyelinating diseases will be facilitated by knowledge of the mechanisms that control its synthesis. These diseases are frequent, and account for considerable morbidity and mortality. However, the regulation of myelination and remyelination is poorly understood. In the PNS, Schwann cells require axonal contact for proliferation, survival, and for the expression of the transcription factor Oct-6, which is required for timely myelination. In claw paw mutant mice, both the segregation of axon fascicles by Schwann cells and their expression of Oct-6 downstream effector genes is delayed, even though Oct-6 is activated normally. Recently, we have identified the genetic defect underlying the claw paw mutation as an insertion in the Lgi4 (Leucine-rich glioma inactivated-4) gene. This gene is expressed by Schwann cells, and encodes a secreted protein of unknown function. Thus Schwann cells secrete a protein that they require for axon segregation, activation of Oct-6 target genes, and myelination. We hypothesize that Lgi4 triggers or modifies axonal or extracellular matrix signal(s), thereby regulating Schwann cell responses to these cues. We propose the following aims to determine how Lgi4 functions in Schwann cell development: 1) Test the hypothesis that Schwann cell differentiation is modulated by the level of Lgi4 expression. 2) Test the hypothesis that Lgi4 controls the expression of essential Schwann cell genes. 3) Test the hypothesis that Lgi4 acts through the Akt/PKB signaling pathway. The experiments summarized above focus on identifying Schwann cell signaling pathways that respond to Lgi4-mediated extracellular signaling;in doing so, we will elucidate the genetic regulatory pathways that result in the formation of peripheral myelin, thereby providing the foundation for new therapies to treat myelination disorders. Relevance: Diseases that affect myelin, such as multiple sclerosis in the central nervous system, and inherited demyelinating neuropathies in the peripheral nervous system, are both debilitating and frequent. By understanding how the Lgi4 protein controls Schwann cell development, we will establish new avenues for the treatment of myelin disorders and nerve injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040751-10
Application #
7991793
Study Section
Neural Degenerative Disorders and Glial Biology Study Section (NDGB)
Program Officer
Owens, David F
Project Start
2001-01-05
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2012-11-30
Support Year
10
Fiscal Year
2011
Total Cost
$352,647
Indirect Cost
Name
Mc Laughlin Research Institute
Department
Type
DUNS #
619471691
City
Great Falls
State
MT
Country
United States
Zip Code
59405
Kegel, Linde; Aunin, Eerik; Meijer, Dies et al. (2013) LGI proteins in the nervous system. ASN Neuro 5:167-81
Rinkevich, Yuval; Mori, Taisuke; Sahoo, Debashis et al. (2012) Identification and prospective isolation of a mesothelial precursor lineage giving rise to smooth muscle cells and fibroblasts for mammalian internal organs, and their vasculature. Nat Cell Biol 14:1251-60
Ozkaynak, Ekim; Abello, Gina; Jaegle, Martine et al. (2010) Adam22 is a major neuronal receptor for Lgi4-mediated Schwann cell signaling. J Neurosci 30:3857-64
Douglas, Darlene S; Moran, Jennifer L; Bermingham Jr, John R et al. (2009) Concurrent Lpin1 and Nrcam mouse mutations result in severe peripheral neuropathy with transitory hindlimb paralysis. J Neurosci 29:12089-100
Bermingham Jr, John R; Shearin, Harold; Pennington, Jamie et al. (2006) The claw paw mutation reveals a role for Lgi4 in peripheral nerve development. Nat Neurosci 9:76-84
Bermingham Jr, John R; Pennington, Jamie (2004) Organization and expression of the SLC36 cluster of amino acid transporter genes. Mamm Genome 15:114-25
Bermingham Jr, John R; Shumas, Susan; Whisenhunt, Tom et al. (2002) Identification of genes that are downregulated in the absence of the POU domain transcription factor pou3f1 (Oct-6, Tst-1, SCIP) in sciatic nerve. J Neurosci 22:10217-31