Ciliary Defects in a Mouse Model of Bardet-Biedl Syndrome are Selectively Pronounced in Brian Regions Involved in...

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.