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.

Grant Number: 1F31DK142351-01
NIH Institute/Center: NIH
Principal Investigator: Kathryn Brewer