Functional POMC Neurons Derived from Tanycytes in the Adult Mouse Hypothalamus
Presentation Number: OR28-1
Date of Presentation: March 20, 2018, 2018
Gabor Wittmann, PhD1, Talisha Sutton, MS2, Malcolm James Low, MD,PHD2, Ronald M. Lechan, MD,PHD1.
1Tufts Medical Center, Boston, MA, USA, 2University of Michigan Med School, Ann Arbor, MI, USA.
Pro-opiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus (Arc) critically regulate feeding behavior, body weight and metabolism. Indirect evidence suggests that as much as 50% of prenatally born Arc POMC neurons may be replaced during adulthood by ongoing neurogenesis (1). Tanycytes, ependymoglial cells that constitute the wall of the third ventricle adjacent to the Arc, function as adult neural stem/progenitor cells and give rise to neurons that populate the Arc (2-4). To test the hypothesis that tanycytes generate POMC neurons during adulthood, we created a mouse model that tracks POMC neurons originating exclusively from tanycytes. In compound RaxCreERT2/+,ArcPomcfneoΔ2/fneoΔ2 mice, tamoxifen-inducible Cre-mediated recombination occurs selectively in hypothalamic tanycytes (5), thus restoring transcriptional activity of the neuronal enhancer region upstream of the Pomc promoter (6). In this model, any Pomc-expressing neurons that appear in the Arc following tamoxifen treatment are derived from tanycytes. In 9 month old obese RaxCreERT2/+,ArcPomcfneoΔ2/fneoΔ2 mice that received tamoxifen treatment at 6 months of age, we observed the emergence of Pomc-expressing neurons in the Arc, equivalent to ~10% of the wild-type number. In association was a loss of up to ~30% of body weight from the mice during the 3 months after tamoxifen treatment, consistent with the effect of reintroduction of Pomc expression into the Arc. The newly generated, tanycyte-derived POMC neurons integrated into the feeding-related circuitry, as POMC-immunoreactive fibers could be observed in both hypothalamic and extra-hypothalamic regions that are normally the targets of POMC neurons. These results establish that a substantial number of POMC neurons originate from tanycytes, and that this is an ongoing phenomenon that occurs throughout adulthood.
References: (1) McNay et al., J Clin Invest. 2012 122:142-152; (2) Lee et al., Nat Neurosci. 2012 15:700-702; (3) Haan et al., J Neurosci. 2013 33:6170-6180; (4) Robins et al., Nat Commun. 2013 4:2049; (5) Pak et al., PLoS ONE. 2014 9:e90381; (6) Bumaschny et al., J Clin Invest. 2012 122:4203-4212.
Research Support: NIH Grant R21AG050663 to RML and MJL.
G. Wittmann: None. T. Sutton: None. M.J. Low: None. R.M. Lechan: None.