👤 C Agassandian

Bardet-Biedl syndrome (BBS) is a human genetic disorder associated with several phenotypes including hypertension. Here we used the hypertensive Bbs4 knockout mouse model (Bbs4-/-) to test the hypothesis that areas of the brain involved in cardiovascular regulation (CVR) exhibit abnormalities in primary neuronal cilia (PNC) structure and density. We utilized immunocytochemical localization of adenylyl cyclase-III (ACIII), a specific marker for PNC, to identify the changes in PNC length and density in commissural nucleus of solitary tract (cNTS), area postrema (AP), rostroventrolateral medulla (RVLM) and subfornical organ (SFO). A quantitative analysis of the morphology and distribution of ACIII-immunoreactive PNC revealed dramatic alterations in the length and number of cilia in SFO of Bbs4-/- mice compared to wild type (WT) littermates. The significant reduction in the PNC length but not in the number was observed in cNTS and RVLM. Surprisingly, no significant changes in length and distribution of PNC were documented in the AP. We found that in all investigated areas of the brain the number of neurons did not display significant changes in Bbs4-/- when compared to the corresponding areas of WT mice. This data suggests that loss of the Bbs4 gene differentially affects the PNC in the brain areas involved in CVR; and the pathology of PNC in selected regions of CVR can cause a failure in signal transduction and may contribute to the hypertension associated with Bbs4-/- mouse model. Show less

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. Show less

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder that results in retinal degeneration, obesity, cognitive impairment, polydactyly, renal abnormalities, and hypogenitalism. Of the 12 known BBS genes, BBS1 is the most commonly mutated, and a single missense mutation (M390R) accounts for approximately 80% of BBS1 cases. To gain insight into the function of BBS1, we generated a Bbs1(M390R/M390R) knockin mouse model. Mice homozygous for the M390R mutation recapitulated aspects of the human phenotype, including retinal degeneration, male infertility, and obesity. The obese mutant mice were hyperphagic and hyperleptinemic and exhibited reduced locomotor activity but no elevation in mean arterial blood pressure. Morphological evaluation of Bbs1 mutant brain neuroanatomy revealed ventriculomegaly of the lateral and third ventricles, thinning of the cerebral cortex, and reduced volume of the corpus striatum and hippocampus. Similar abnormalities were also observed in the brains of Bbs2(-/-), Bbs4(-/-), and Bbs6(-/-) mice, establishing these neuroanatomical defects as a previously undescribed BBS mouse model phenotype. Ultrastructural examination of the ependymal cell cilia that line the enlarged third ventricle of the Bbs1 mutant brains showed that, whereas the 9 + 2 arrangement of axonemal microtubules was intact, elongated cilia and cilia with abnormally swollen distal ends were present. Together with data from transmission electron microscopy analysis of photoreceptor cell connecting cilia, the Bbs1 M390R mutation does not affect axonemal structure, but it may play a role in the regulation of cilia assembly and/or function. Show less