How Loss of Neurofibromin in Oligodendrocytes Affects the Brain

Mayes D.A.,Rizvi T.A., Kolasinski N., Miller S.,& Ratner N.
Department of Experimental Hematology & Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati OH

Neurofibromatosis type 1 patients are predisposed to central nervous system (CNS) phenotypes including enlarged brains, delayed acquisition of motor skills, brain tumors, and cognitive deficits.  Imaging and pathologic analysis suggest that changes in white matter myelination may underlie both the enlargement of white matter tracts that contributes to megancephaly, and/or hyper-intense signals visualized on MRI. To study the role(s) of Nf1 and HRasin oligodendrocytes, we examined the optic nerve and corpus callosum,myelinated fiber tracts.We studiedNf1heterozygous mice,tamoxifen-induced Nf1 loss in mature oligodendrocytes (Plp-CreERT), and a new transgenic model in which the CNPase promoter drives expression of HRasG12V. Activated HRas and loss of Nf1 within oligo-lineage cells (PLPCre; Nf1fl+; &PLPCre; Nf1fl/fl) resulted in optic nerve enlargement. The corpus callosum of CNP-HRasG12V mice was also enlarged. Electron microscopy analysis revealed 3 phenotypes within the enlarged optic nerves. 1)When Nf1 was lost or HRas was activated within oligodendrocytes, the myelin was decompacted due to splitting at the intraperiod lines. The transgenic Nf1+/- mice, in which Nf1 loss is not restricted to oligo-lineage cells, displayed lesser myelin decompaction, and these mice did not have significantly enlarged optic nerves. 2) Enlarged axons accompanied the decompacted myelin within all models. 3) All Nf1 and Ras mouse models also showed an expansion of the perivascular astrocyticendfeet surrounding the vasculature. These phenotypes were also found within the corpus callosum. Thus, myelin and vascular phenotypesare not limited to a single myelinated fiber tract. These studies reveal a cell autonomous role for the Nf1/Ras pathway in the regulation of myelin compaction, and a non-cell autonomous role in the regulation of astrocyticendfeet surrounding brain capillaries.

Supported by: DOD Program on Neurofibromatosis (W81XWH-06-1-0114) &

NIH (R01-NS28840 ) to N.R.; NIH NRSA (T32CA117846) & NMSS (FG1762A1/1) Post-doctoral Fellowships to D.A.M.