Hypothalamic proopiomelanocortin (POMC) neurons are critical regulators of feeding behavior and energy balance in both rodents and humans. As tanycytes, ependymoglial cells that constitute the wall of the third ventricle adjacent to the arcuate nucleus, synthesize POMC and may function as adult, neural stem/progenitor cells, we hypothesized that they are capable of maturing into POMC neurons that populate the arcuate nucleus. To test this possibility, we created a mouse model, the RaxCreERT2/+/ArcPomcfneo/fneo mouse, in which POMC-expressing neurons would only appear in the arcuate nucleus following tamoxifen treatment if any derive from tanycytes. Our preliminary data demonstrate that ~10% of the normal population of Pomc- expressing neurons in the arcuate nucleus originate from tanycytes when tamoxifen is administered between ages 6 and 9 months, associated with partial reversal of the obese phenotype of ArcPomcfneo/fneoKO mice. To elucidate the mechanisms by which this transformation takes place, we propose to study the transcriptome by RNA-Seq analysis of tanycyte-derived, adult-born POMC neurons, singly isolated by laser capture microdissection, and compare to the rest of the arcuate nucleus POMC neuronal population and to tanycytes. This will be accomplished using a RaxCreERT2/Ai9/Pomc-EGFP mouse model in which the population of POMC neurons derived from tanycytes following tamoxifen treatment can be distinguished from all other POMC neurons and tanycytes by their fluorescence characteristics. To determine the appropriate age following tamoxifen administration to isolate POMC neurons derived from tanycytes at their earliest timepoint, initial studies will be conducted using the RaxCreERT2/+/ArcPomcfneo/fneo model and both in situ hybridization histochemistry and immunocytochemistry to determine the age of peak POMC neuronal generation and the time course by which tanycytes differentiate into POMC neurons and integrate into the feeding-related circuitry. We propose the studies could provide important, new information about POMC neurogenesis that could lead to a novel approach to treat obesity and the age-related decline of adult, hypothalamic POMC neurons.
We recently demonstrated that tanycytes have the capacity to generate mature, functioning, POMC neurons in the adult brain that can migrate to their natural loci in the mediobasal hypothalamus and integrate into the feeding-related circuitry. The proposed studies will further characterize these cells with the main goal of elucidating factors that permit tanycytes to generate POMC neurons. We propose that understanding the mechanisms by which this transformation takes place may ultimately lead to a novel approach to treat obesity.
