Development of hydrocephalus in mice expressing the G(i)-coupled GPCR Ro1 RASSL receptor in astrocytes.
We developed a transgenic mouse line that expresses the G(i)-coupled RASSL (receptor activated solely by synthetic ligand) Ro1 in astrocytes to study astrocyte-neuronal communication. Surprisingly, we found that all transgenics expressing Ro1 developed hydrocephalus. We analyzed these mice in an effort to develop a new model of hydrocephalus that will further our understanding of the pathophysiology of the disease. Expression of Ro1 was restricted to astrocytes by crossing the transgenic hGFAP-tTA (tet transactivator behind the human glial fibrillary acidic protein promoter) mouse line with the transgenic tetO-Ro1/tetO-LacZ mouse line. This cross produced double-transgenic mice that expressed Ro1 in astrocytes. All double transgenics developed hydrocephalus by postnatal day 15, whereas single-transgenic littermate controls appeared normal. Hydrocephalic Ro1 mice displayed enlarged ventricles, partial denudation of the ependymal cell layer, altered subcommissural organ morphology, and obliteration of the cerebral aqueduct. Severely hydrocephalic mice also had increased levels of phospho-Erk and GFAP expression. Administration of doxycycline to breeding pairs suppressed Ro1 expression and the onset of hydrocephalus in double-transgenic offspring. Ro1 animals maintained on dox did not develop hydrocephalus; however, if taken off doxycycline at weaning, double-transgenic mice developed enlarged ventricles within 7 weeks, indicating that Ro1 expression also induces hydrocephalus in adults. This study discovered a new model of hydrocephalus in which the rate of pathogenesis can be controlled enabling the study of the pathogenesis of both juvenile and adult onset hydrocephalus.
Sweger
Elizabeth J
EJ
Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Casper
Kristen B
KB
Scearce-Levie
Kimberly
K
Conklin
Bruce R
BR
McCarthy
Ken D
KD
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D004318:Doxycycline; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006849:Hydrocephalus / Q000235:genetics* / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D015854:Up-Regulation
D005904:Glial Fibrillary Acidic Protein; D017473:Receptors, Opioid, kappa; C110260:Ro1 protein, synthetic; D004318:Doxycycline