Loss of Bardet - Biedl syndrome protein-8 (BBS8) perturbs olfactory function, protein localization, and axon targeting

Abigail L.D. Tadenev, Heather M. Kulaga, Helen L. May-Simera, Matthew W. Kelley, Elias Nicholas Katsanis, Randall R. Reed

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Bardet - Biedl syndrome (BBS) is a pleiotropic, heterogeneous human disease whose etiology lies primarily in dysfunctional basal bodies and/or cilia. Both BBS patients and several BBS mouse models exhibit impaired olfactory function. To explore the nature of olfactory defects in BBS, a genetic ablation of the mouse Bbs8 gene that incorporates a fluorescent reporter protein was created. The endogenous BBS8 protein and reporter are particularly abundant in olfactory sensory neurons (OSNs), and specific BBS8 antibodies reveal staining in the dendritic knob in a shell-like structure that surrounds the basal bodies. Bbs8-null mice have reduced olfactory responses to a number of odorants, and immunohistochemical analyses reveal a near-complete loss of cilia from OSNs and mislocalization of proteins normally enriched in cilia. To visualize altered protein localization in OSNs, we generated a SLP3 eGFP knock-in mouse and imaged the apical epithelium, including dendritic knobs and proximal cilia, in ex vivo tissue preparations. Additionally, protein reagents that reflect the characteristic neuronal activity of each OSN revealed altered activity in Bbs8-null cells. In addition to previously known defects at the ciliary border, we also observed aberrant targeting of OSN axons to the olfactory bulb; axons expressing the same receptor display reduced fasciculation and project to multiple targets in the olfactory bulb.Wesuggest that loss of BBS8 leads to a dramatic and variable reduction in cilia, the essential signaling platform for olfaction, which alters the uniformity of responses in populations of OSNs expressing the same receptor, thereby contributing to the observed axon-targeting defects.

Original languageEnglish (US)
Pages (from-to)10320-10325
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number25
DOIs
StatePublished - Jun 21 2011

Keywords

  • Ciliopathy
  • Olfactory activity
  • Protein trafficking

ASJC Scopus subject areas

  • General

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