Ciliopathy Is Differentially Distributed in the Brain of a Bardet-Biedl Syndrome Mouse Model

Abstract

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.

BBS4 is required for IFT coordination and basal body number in mammalian olfactory cilia.

“…This complexity is highlighted by the fact that cilia are not lost in all tissues of Bbs4-null animals. Cilia persist in the amygdala and hippocampus within the brain and in the renal cells of the kidney in Bbs4 −/− mutant mice (Agassandian et al, 2014;Berbari et al, 2008;Mokrzan et al, 2007;Mykytyn et al, 2004). Within the nasal cavity, respiratory cells were not affected by the loss of BBS4, corroborating prior structural and functional studies (Kulaga et al, 2004;Shah et al, 2008).…”

“…These observations support the idea that basal body reduction is not concomitant to cilia loss. However, because cilia and basal bodies appeared structurally intact in hippocampal and amygdala neurons, as well as multiciliated cells in Bbs4 −/− mutant mice (Agassandian et al, 2014;Shah et al, 2008;Swiderski et al, 2012), the impact of BBS4 loss on OSNs basal bodies could be unique to these neurons. It is possible that OSNs utilize alternative mechanisms for basal body biogenesis and maintenance that makes the neurons sensitive to loss in the absence of BBS4.…”

Brain Dysplasia Associated with Ciliary Dysfunction in Infants with Congenital Heart Disease

“…[44, 45] Hippocampal abnormalities also are observed in BBS patients and mouse models of BBS. [46] Abnormalities involving the corpus callosum, such as in acrocallosal syndrome, are associated with mutations affecting cilia transduced cell signaling. [47]…”

Exploration of the cognitive, adaptive and behavioral functioning of patients affected with Bardet–Biedl syndrome

“…The recent identification of BBS genes as risk factors for ASD and the heightened incidence of patients with ASD symptoms in our sample of BBS patients, warrant further studies on the relationship between autism and BBS. Although the brain imaging studies of BBS patients are incomplete, data available from humans and the bbs animal models identified changes that may cause learning, behavior, and memory deficits . Future studies on the association of brain imagining changes and neuropsychological functioning should provide valuable information.…”