Effects of irradiation on the postnatal development of the brain in a genetic mouse model of globoid cell leukodystrophy.
Irradiation is one way to condition Twitcher mice--a natural model of globoid cell leukodystrophy (GLD)--prior to receive bone marrow transplantation (BMT). BMT showed to delay but not to completely prevent GLD disease in treated mutants. The reasons why BMT is not completely preventive in Twitchers are unclear but we speculate that irradiation might contribute to worsen the neurological impairments generated by the disease by altering postnatal neurogenesis. To test this hypothesis, we examined proliferation, migration and differentiation of neural precursors in neurogenic areas of the Twitcher brain after exposure of 5 day-old mutant pups to 620 rad, a non-lethal dose that leads to 80-90% of bone-marrow engraftment in classic BMT. Twitchers showed to be sensitive to irradiation, leading to a severe retardation of body growth of irradiated mutants. Irradiated Twitchers had reduced proliferation of neural precursors and increased astrogliosis and microgliosis, with reduced numbers of migratory neuroblasts and significantly less brain myelination. These effects were accompanied by caspase-3 activation and appeared largely irreversible in the lifespan of the Twitcher. Our work confirms that exposure of the neonatal brain to irradiation conditions such as those performed prior to BMT, can lead to long-lasting alterations of postnatal neurogenesis and myelination, which might contribute to worsen the progression of disease in these myelin mutants and to reduce the success of BMT.
Galbiati
Francesca
F
San Raffaele Scientific Institute, Via Olgettina 58, Milano 20132, Italy.
Clementi
Giulia
G
Superchi
Daniela
D
Givogri
Maria I
MI
Bongarzone
Ernesto R
ER
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D016026:Bone Marrow Transplantation; D001921:Brain / Q000166:cytology / Q000254:growth & development* / Q000528:radiation effects*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000528:radiation effects; D004195:Disease Models, Animal; D005720:Gamma Rays; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007965:Leukodystrophy, Globoid Cell / Q000503:physiopathology*; D008264:Macrophages / Q000528:radiation effects; D051379:Mice; D008818:Mice, Neurologic Mutants; D018991:Myelin Proteolipid Protein / Q000096:biosynthesis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009457:Neuroglia / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000502:physiology / Q000528:radiation effects
D005904:Glial Fibrillary Acidic Protein; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; C047516:Plp1 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3