Cilia-mediated Proliferation in Hypothalamic Tanycytes

PROJECT SUMMARY Obesity promotes heart disease and diabetes; both causes of early mortality. Most adults in the United States are overweight, and obesity adds cost to healthcare. Mechanisms regulating energy homeostasis are not completely understood. Recently, small cell appendages in the brain called cilia were shown to be essential to prevent overeating and obesity. Primary cilia are critical for proper cell-to-cell communication. The best understood cilia-mediated signaling pathway is Hedgehog (HH) signaling. During development, HH is essential for the patterning of many tissues. Our lab has discovered that the components of the HH pathway continue to be expressed in the adult hypothalamus and both feeding status and body composition dynamically regulate hypothalamic HH signaling. Moreover, we found that genetically activating HH signaling in specific cell types causes hyperphagia and obesity. Thus, HH signals are redeployed after embryonic development to influence adult feeding behavior and energy homeostasis. I seek to build on these insights to determine how HH signaling in the hypothalamus controls long-term energy homeostasis. I have chosen to focus on a specific cell type in the hypothalamus, called tanycytes. Tanycytes line the third ventricular space extending their processes deep within the hypothalamus. Interestingly, tanycytes undergo cell proliferation during early postnatal development. They also proliferate in response to extreme changes in feeding status and body composition. My preliminary data shows that tanycytes express and localize several HH pathway components to their cilia. Thus, I hypothesize that HH signals regulate tanycyte proliferation during postnatal development which is required for proper adult energy homeostasis. I will test these hypotheses using complementary in vitro (Aim 1) and in vivo (Aim 2) approaches. Together, the experiments in this project test whether ciliary HH signaling induces tanycyte proliferation needed for regulating long-term energy homeostasis.