PMID- 27923908
OWN - NLM
STAT- MEDLINE
DCOM- 20170810
LR  - 20190627
IS  - 1540-9538 (Electronic)
IS  - 0022-1007 (Print)
IS  - 0022-1007 (Linking)
VI  - 214
IP  - 1
DP  - 2017 Jan
TI  - Estrogen activation of microglia underlies the sexually dimorphic differences in 
      Nf1 optic glioma-induced retinal pathology.
PG  - 17-25
LID - 10.1084/jem.20160447 [doi]
AB  - 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-beta 
      (ERbeta) 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.
CI  - (c) 2017 Toonen et al.
FAU - Toonen, Joseph A
AU  - Toonen JA
AD  - Department of Neurology, Washington University School of Medicine, St. Louis, MO 
      63110.
FAU - Solga, Anne C
AU  - Solga AC
AD  - Department of Neurology, Washington University School of Medicine, St. Louis, MO 
      63110.
FAU - Ma, Yu
AU  - Ma Y
AD  - Department of Neurology, Washington University School of Medicine, St. Louis, MO 
      63110.
FAU - Gutmann, David H
AU  - Gutmann DH
AD  - Department of Neurology, Washington University School of Medicine, St. Louis, MO 
      63110 gutmannd@wustl.edu.
LA  - eng
GR  - R01 CA195692/CA/NCI NIH HHS/United States
GR  - R01 CA214146/CA/NCI NIH HHS/United States
GR  - T32 NS007205/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20161206
PL  - United States
TA  - J Exp Med
JT  - The Journal of experimental medicine
JID - 2985109R
RN  - 0 (Estrogen Receptor beta)
RN  - 0 (Estrogens)
SB  - IM
MH  - Animals
MH  - Estrogen Receptor beta/physiology
MH  - Estrogens/*pharmacology
MH  - Female
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Microglia/*drug effects
MH  - Nerve Fibers/pathology
MH  - Neurofibromatosis 1/*pathology
MH  - Optic Nerve Glioma/*pathology
MH  - Retina/*pathology
MH  - Retinal Ganglion Cells/pathology
MH  - Sex Characteristics
PMC - PMC5206494
EDAT- 2016/12/08 06:00
MHDA- 2017/08/11 06:00
PMCR- 2017/07/01
CRDT- 2016/12/08 06:00
PHST- 2016/03/29 00:00 [received]
PHST- 2016/09/23 00:00 [revised]
PHST- 2016/11/11 00:00 [accepted]
PHST- 2016/12/08 06:00 [pubmed]
PHST- 2017/08/11 06:00 [medline]
PHST- 2016/12/08 06:00 [entrez]
PHST- 2017/07/01 00:00 [pmc-release]
AID - jem.20160447 [pii]
AID - 20160447 [pii]
AID - 10.1084/jem.20160447 [doi]
PST - ppublish
SO  - J Exp Med. 2017 Jan;214(1):17-25. doi: 10.1084/jem.20160447. Epub 2016 Dec 6.