Ciliopathy is differentially distributed in the brain of a Bardet-Biedl syndrome mouse model.
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous inherited human disorder displaying a pleotropic phenotype. Many of the symptoms characterized in the human disease have been reproduced in animal models carrying deletions or knock-in mutations of genes causal for the disorder. Thinning of the cerebral cortex, enlargement of the lateral and third ventricles, and structural changes in cilia are among the pathologies documented in these animal models. Ciliopathy is of particular interest in light of recent studies that have implicated primary neuronal cilia (PNC) in neuronal signal transduction. In the present investigation, we tested the hypothesis that areas of the brain responsible for learning and memory formation would differentially exhibit PNC abnormalities in animals carrying a deletion of the Bbs4 gene (Bbs4-/-). Immunohistochemical localization of adenylyl cyclase-III (ACIII), a marker restricted to PNC, revealed dramatic alterations in PNC morphology and a statistically significant reduction in number of immunopositive cilia in the hippocampus and amygdala of Bbs4-/- mice compared to wild type (WT) littermates. Western blot analysis confirmed the decrease of ACIII levels in the hippocampus and amygdala of Bbs4-/- mice, and electron microscopy demonstrated pathological alterations of PNC in the hippocampus and amygdala. Importantly, no neuronal loss was found within the subregions of amygdala and hippocampus sampled in Bbs4-/- mice and there were no statistically significant alterations of ACIII immunopositive cilia in other areas of the brain not known to contribute to the BBS phenotype. Considered with data documenting a role of cilia in signal transduction these findings support the conclusion that alterations in cilia structure or neurochemical phenotypes may contribute to the cognitive deficits observed in the Bbs4-/- mouse mode.
Department of Neuroscience, the University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Khristofor
K
Agassandian
Department of Neuroscience, the University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Milan
M
Patel
Department of Medicine, the University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Marianna
M
Agassandian
Department of Neuroscience, the University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Karina E
KE
Steren
Departments of Pharmacology and Internal Medicine, the University of Iowa, Iowa City, Iowa, United States of America.
Kamal
K
Rahmouni
Department of Pediatrics, the University of Iowa, Iowa City, Iowa, United States of America; Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa, United States of America.
Val C
VC
Sheffield
Department of Neuroscience, the University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
J Patrick
JP
Card
D000262:Adenylyl Cyclases / Q000378:metabolism; D000679:Amygdala / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000378:metabolism / Q000473:pathology*; D002923:Cilia / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism
C506281:BBS4 protein, mouse; D008869:Microtubule-Associated Proteins; D000262:Adenylyl Cyclases