The Role of Vitamin D on Cell Proliferation in the Olfactory System and the Brain

Abstract

The clear evidence that vitamin D (referring to the hormonally active form 1,25-dixydroxyvitamin D3 all through this thesis) is involved in brain development and the widespread distribution of the VDR in neurogenic regions of the brain, propose that vitamin D may be an important regulator of neural stem and progenitor cell proliferation. The inhibitory effect of vitamin D on cell proliferation is well characterised in a wide variety of tissues. Nevertheless, little is known about the effect of vitamin D on neural stem/progenitor cell proliferation. The olfactory tissue is a well-established model for molecular factors and genes that regulate neurogenesis. The ability of the olfactory epithelium to be grown as primary cultures, to give rise to a mixture of neuronal precursors and developing neurons, and the finding that it contains multipotent stem cells (Murrel et al, 1996, 2005; Féron et al, 1998; Newman et al, 2000; McCurdy et al, 2005), make this tissue a good model for investigating the effects of vitamin D on olfactory neurogenesis. The overall aim of this thesis was to explore the effect of vitamin D on stem and progenitor cell proliferation in the olfactory system and the brain. This was achieved by using two different animal models. One model explored the effect on neurosphere formation in animals deprived of vitamin D during development (developmental vitamin D (DVD) deficiency). The other model used genetically modified animals that had a dysfunctional VDR (VDR knockout animals) to investigate the effect of vitamin D inactivation on stem and progenitor cell proliferation in the olfactory system and the brain. Here it was found that DVD deficiency increased the number of neurospheres formed in cultures from the adult olfactory mucosa. Exogenous vitamin D added to the culture medium had no effect on olfactory neurosphere formation in the DVD cultures but it reduced the neurosphere diameter in the controls. Vitamin D reduced olfactory neurosphere number in the VDR KO animals but had no effect on their size. This thesis also shows that the lack of a functional VDR reduced cell proliferation in the adult mouse brain and olfactory system in vivo. These results demonstrate that vitamin D can regulate stem and progenitor cell proliferation in the olfactory system and the brain and provide a foundation for further investigations into the molecular basis underlying the physiological abnormalities associated with vitamin D deficiency and disruption of vitamin D signalling through VDR inactivation.