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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Estrogen activation of microglia underlies the sexually dimorphic differences in Nf1 optic glioma-induced retinal
Joseph A Toonen1, Anne C Solga1, Yu Ma1
1Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110.
Abstract:
Children with neurofibromatosis type 1 (NF1) develop low-grade brain tumors throughout the optic pathway. Nearly 50% of children with optic pathway gliomas (OPGs) experience visual impairment, and few regain their vision after chemotherapy. Recent studies have revealed that girls with optic nerve gliomas are five times more likely to lose vision and require treatment than boys. To determine the mechanism underlying this sexually dimorphic difference in clinical outcome, we leveraged Nf1 optic glioma (Nf1-OPG) mice. We demonstrate that female Nf1-OPG mice exhibit greater retinal ganglion cell (RGC) loss and only females have retinal nerve fiber layer (RNFL) thinning, despite mice of both sexes harboring tumors of identical volumes and proliferation. Female gonadal sex hormones are responsible for this sexual dimorphism, as ovariectomy, but not castration, of Nf1-OPG mice normalizes RGC survival and RNFL thickness. In addition, female Nf1-OPG mice have threefold more microglia than their male counterparts, and minocycline inhibition of microglia corrects the retinal pathology. Moreover, pharmacologic inhibition of microglial estrogen receptor-β (ERβ) function corrects the retinal abnormalities in female Nf1-OPG mice. Collectively, these studies establish that female gonadal sex hormones underlie the sexual dimorphic differences in Nf1 optic glioma-induced retinal dysfunction by operating at the level of tumor-associated microglial activation.
Insights
Female sex hormones worsen vision loss in children with neurofibromatosis type 1 (NF1) optic pathway gliomas (OPGs). This occurs through increased microglial activation in the retina, leading to greater vision impairment in girls.
Area of Science:
- Neuro-oncology
- Ophthalmology
- Endocrinology
Background:
- Neurofibromatosis type 1 (NF1) is associated with optic pathway gliomas (OPGs).
- OPGs cause visual impairment in nearly 50% of affected children.
- Girls with OPGs experience significantly worse vision loss than boys.
Purpose of the Study:
- To investigate the mechanism behind the sexual dimorphism in vision loss for pediatric OPGs.
- To identify the role of gonadal sex hormones and microglia in OPG-induced retinal damage.
Main Methods:
- Utilized Nf1 optic glioma (Nf1-OPG) mouse models.
- Performed ovariectomy and castration experiments.
- Assessed retinal ganglion cell (RGC) loss and retinal nerve fiber layer (RNFL) thickness.
- Investigated microglial activation and estrogen receptor-beta (ERβ) function.
Main Results:
- Female Nf1-OPG mice showed greater RGC loss and RNFL thinning than males, despite similar tumor burden.
- Ovariectomy, but not castration, normalized retinal pathology in female mice.
- Female mice had increased microglia, and minocycline treatment corrected retinal abnormalities.
- Inhibiting microglial ERβ function ameliorated retinal damage in females.
Conclusions:
- Female gonadal sex hormones drive sexual dimorphism in OPG-related vision loss.
- This dimorphism is mediated by enhanced microglial activation in the retina.
- Targeting microglial ERβ may offer therapeutic potential for vision preservation in NF1 patients.
