Defining vitamin D receptor expression in the brain using a novel VDRCre mouse

Authors: LIU, HAILAN - Children'S Nutrition Research Center (CNRC); HE, YANG - Children'S Nutrition Research Center (CNRC); BECK, JESSIE - Children'S Nutrition Research Center (CNRC); DA SILVA TEIXEIRA, SILVANIA - University Of Colorado; HARRISON, KEISHA - Oregon State University; XU, YONG - Children'S Nutrition Research Center (CNRC); SISLEY, STEPHANIE - Children'S Nutrition Research Center (CNRC)

Submitted to: Journal of Comparative Neurology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/14/2020
Publication Date: 12/25/2020
Citation: Liu, H., He, Y., Beck, J., Da Silva Teixeira, S., Harrison, K., Xu, Y., Sisley, S. 2020. Defining vitamin D receptor expression in the brain using a novel VDRCre mouse. Journal of Comparative Neurology. https://doi.org/10.1002/cne.25100.
DOI: https://doi.org/10.1002/cne.25100

Interpretive Summary: Low vitamin D levels are associated with both diabetes and obesity but how vitamin D might impact these two diseases is unknown. Understanding how vitamin D affects blood sugar or weight regulation is important in order to use it as a possible treatment. Previous work has shown that the brain is a critical region for both blood sugar and weight control. Additionally, data indicated that action of vitamin D occurred through the vitamin D receptor in the brain. However, we did not know what types of cells in the brain were important for vitamin D action because the available methods to identify the vitamin D receptor were not useful in the brain. In this paper, we created a new mouse to identify the vitamin D receptor-containing cells in the brain. We show that the vitamin D receptor is in key regions of the brain important for blood sugar and weight control, as well as many other brain regions important for memory and mental health. We also show that within a key area of the brain important for vitamin D action on glucose control (the paraventricular hypothalamus), there are many cells that have the vitamin D receptor but are not cells that also contain oxytocin or vasopressin (2 major markers within that brain area). Additionally, we show that these identified cells with the vitamin D receptor respond to vitamin D with rapid electrical activity. This is the first paper describing a new mouse model to identify vitamin D receptor cells in the body and validating these cells in brain to be responsive to vitamin D. This paper provides validation of a useful tool to the study of vitamin D receptors.

Technical Abstract: Vitamin D action has been linked to several diseases regulated by the brain including obesity, diabetes, autism, and Parkinson's. However, the location of the vitamin D receptor (VDR) in the brain is not clear due to conflicting reports. We found that two antibodies previously published as specific in peripheral tissues are not specific in the brain. We thus created a new knockin mouse with cre recombinase expression under the control of the endogenous VDR promoter (VDRCre ). We demonstrated that the cre activity in the VDRCre mouse brain (as reported by a cre-dependent tdTomato expression) is highly overlapping with endogenous VDR mRNAs. These VDR-expressing cells were enriched in multiple brain regions including the cortex, amygdala, caudate putamen, and hypothalamus among others. In the hypothalamus, VDR partially colocalized with vasopressin, oxytocin, estrogen receptor-a, and ß-endorphin to various degrees. We further functionally validated our model by demonstrating that the endogenous VDR agonist 1,25-dihydroxyvitamin D activated all tested tdTomato+ neurons in the paraventricular hypothalamus but had no effect on neurons without tdTomato fluorescence. Thus, we have generated a new mouse tool that allows us to visualize VDR-expressing cells and to characterize their functions.