title: BBS4 is necessary for ciliary localization of TrkB receptor and activation by BDNF.
abstract: Primary cilia regulate an expanding list of signaling pathways in many different cell types. It is likely that identification of the full catalog of pathways associated with cilia will be necessary to fully understand their role in regulation of signaling and the implications for diseases associated with their dysfunction, ciliopathies. Bardet-Biedl Syndrome (BBS) is one such ciliopathy which is characterized by a spectrum of phenotypes. These include neural defects such as impaired cognitive development, centrally mediated hyperphagia and peripheral sensory defects. Here we investigate potential defects in a signaling pathway associated with neuronal function, brain derived neurotrophic factor (BDNF) signaling. Upon loss of BBS4 expression in cultured cells, we observed decreased phosphorylation and activation by BDNF of its target receptor, TrkB. Assessment of ciliary localization revealed that, TrkB localized to the axonemes or basal bodies of cilia only in the presence of BDNF. Axonemal localization, specifically, was abrogated with loss of BBS4. Finally, we present evidence that loss of the ciliary axoneme through depletion of KIF3A impedes activation of TrkB. Taken together, these data suggest the possibility of a previously uninvestigated pathway associated with perturbation of ciliary proteins.
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Leitch
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Norann A
authors.initials: NA
authors.lastname: Zaghloul
mesh_terms: D054468:Axoneme / Q000378:metabolism; D064652:Basal Bodies / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002460:Cell Line; D002923:Cilia / Q000378:metabolism*; D006801:Humans; D016547:Kinesins / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020813:Receptor, trkB; D015398:Signal Transduction
chemical_list: C429655:BBS4 protein, human; D019208:Brain-Derived Neurotrophic Factor; C087415:KIF3A protein, human; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D011506:Proteins; C579455:BDNF protein, human; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human; D016547:Kinesins