title: Nuclear lipid microdomains regulate nuclear vitamin D3 uptake and influence embryonic hippocampal cell differentiation.
abstract: Despite recent advances in the understanding of the role of 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) in the CNS, the mechanism of action remains obscure. We demonstrate that some 1,25-(OH)(2)D(3) receptor (VDR) is localized in the cell nucleus in specialized microdomains enriched in sphingomyelin and cholesterol; the integrity of these microdomains is necessary for embryonic hippocampal cell differentiation. Sphingomyelinase (SMase) treatment reduces both VDR and labeled 1,25-(OH)(2)D(3) content in nuclear microdomains. We have previously shown that HN9.10e embryonic hippocampal cells differentiate when incubated with 100 nM 1,25-(OH)(2)D(3) in the presence of 10% fetal calf serum, while serum deprivation induces cell death. In this study, we have investigated whether conditions that alter lipid content of nuclear microdomains modify 1,25-(OH)(2)D(3)-induced differentiation. Serum deprivation activates SMase and modifies the composition of nuclear microdomains, which lose the 1,25-(OH)(2) vitamin D(3) receptor. The incubation of serum-deprived cells with 100 nM 1,25-(OH)(2)D(3) prevents differentiation. However, treatment with 400 nM 1,25-(OH)(2)D(3) during serum withdrawal increases the lipid content of the nuclear microdomains, allows the interaction of 1,25-(OH)(2)D(3) with its receptor, and results in differentiation. These results suggest the presence of VDR in nuclear microdomains is necessary for 1,25-(OH)(2)D(3)-induced differentiation in embryonic hippocampal cells.
authors: Physiopathology Section, Department of Clinical and Experimental Medicine, University School of Medicine, University of Perugia, Perugia, Italy. ealbi@unipg.it
authors: Elisa
authors: E
authors: Bartoccini
authors: Francesca
authors: F
authors: Marini
authors: Eleni
authors: E
authors: Damaskopoulou
authors: Remo
authors: R
authors: Lazzarini
authors: Samuela
authors: S
authors: Cataldi
authors: Giacomo
authors: G
authors: Cascianelli
authors: Mercedes
authors: M
authors: Gil Garcia
authors: Elisabetta
authors: E
authors: Albi
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D048430:Cell Shape; D002762:Cholecalciferol / Q000494:pharmacology* / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D050356:Lipid Metabolism; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D020932:Nerve Growth Factor / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D018167:Receptors, Calcitriol / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000494:pharmacology / Q000502:physiology; D013109:Sphingomyelins / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018167:Receptors, Calcitriol; D013109:Sphingomyelins; C052617:Bcl2 protein, mouse; D002762:Cholecalciferol; D020932:Nerve Growth Factor; D013108:Sphingomyelin Phosphodiesterase