Primary cilia were long thought to be vestigial organelles serving no real purpose in mammalian systems. We now know that cilia serve diverse roles in mammalian development and adult homeostasis through their ability to coordinate specific signaling pathways. Our lab is broadly interested in how dysfunctional cilia are involved in human health and disease. Cilia dysfunction is associated with a growing group of rare genetic disorders collectively called the ciliopathies. By studying models of ciliopathies we will reveal more about their basic biology and ultimately contribute to our understanding of .the more common clinical features observed in the ciliopathies such as obesity, retinal degeneration and cognitive deficits.
Neuronal Cilia and Obesity
Primary cilia dysfunction is associated with hyperphagia and obesity in ciliopathies and animal models. More specifically, when cilia are disrupted in the feeding centers of the brain this results in the obesity phenotype. We are trying to determine how cilia can affect appetite and satiety. We are utilizing conditional and congenital knockout mouse models, tissue culture, pharmacology and electrophysiology to address this question. Current studies are focused on looking at the roles of cilia associated signaling in specific neuronal populations in the hypothalamus.
- Berbari N.F.#, Pasek R.C.#, Malarkey E.B., Yazdi S.M.Z. R., McNair A., Lewis W.R., Kesterson R.A., Nagy T., Yoder B.K. Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice. Proc Natl Acad Sci U S A. 2013 May 7; 110 (19):7796-81. PMCID: PMC3651481 http://www.ncbi.nlm.nih.gov/pubmed/23599282
- Berbari N.F., Pasek R.C., Yoder B.K. Neuronal Cilia in Obesity. Chapter in “Cilia in Neuroscience” Springer Press. 2013.
Cilia and Behavior
Primary cilia are present on most cells in the central nervous system yet their impacts on behaviors remain largely unknown. An ongoing interest in the lab is to determine the potential roles of cilia in other behaviors such as addiction and reward, learning and memory and sleep.
- Berbari N.F. #, Malarkey E.B. #, Yazdi S.M.Z. R., McNairA.D., CroyleM.J., KraftT.W., YoderB.K. Hippocampal and Cortical Primary Cilia are Required for Aversive Memory. PLoS One. 2014 Sep 3;9(9):e106576. doi: 10.1371/journal.pone.0106576. eCollection 2014. PMCID: PMC4153651 http://www.ncbi.nlm.nih.gov/pubmed/25184295
Neurodevelopment and Cilia
Cilia are known to be critical for mammalian development largely through their role in coordinating the hedgehog signaling pathway. One interesting question is how do subtle perturbations in cilia mediated hedgehog signaling affect both neurodevelopment and subsequent adult behaviors.
- Sharma N.,Berbari N.F., Yoder B.K. Ciliary Dysfunction in Developmental Abnormalities and Disease. Curr Top Dev Biol. 2008;85: 371-427. Review. http://www.ncbi.nlm.nih.gov/pubmed/19147012
- Berbari N.F., Kin N.W., Sharma N., Michaud E.J., Kesterson R.A., Yoder B.K. Mutations in Traf3ip1 reveal defects in ciliogenesis, embryonic development, and altered cell size regulation. Dev Biol. 2011 Dec 1; 360 (1):66-76. PMCID: PMC4059607. http://www.ncbi.nlm.nih.gov/pubmed/21945076
- Pasek R.C., Berbari N.F., Kesterson R.A., and Yoder B.K. Mammalian Clusterin associated protein 1 is an evolutionarily conserved protein required for ciliogenesis. Cilia. 2012 Nov 1; 1 (1):20. PMCID: PMC3556011. http://www.ncbi.nlm.nih.gov/pubmed/23351563