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Divergent roles of 25-hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3 in neural fate determination: A CYP27B1-dependent neuron formation and VDR-dependent astrocyte development

Year: 2025

Type: article

Abstract: Vitamin D plays a crucial role in neural differentiation, yet its precise mechanisms remain unclear. In this study, we investigated the effects of vitamin D metabolites, 25-hydroxyvitamin D 3 (25D 3 ) and 1α,25-dihydroxyvitamin D 3 (1α,25D 3 ), on neural differentiation using Cyp27b1 −/− and Vdr −/− knockout mice-derived neural stem cells. We found that 1α,25D 3 promotes neuronal differentiation via vitamin D receptor (VDR), whereas some of its effects occur independently of VDR. Additionally, 25D 3 requires conversion to 1α,25D 3 by CYP27B1 to induce neuronal differentiation. In contrast, both 25D 3 and 1α,25D 3 promoted astrocyte differentiation regardless of CYP27B1 expression but required VDR. Furthermore, using vitamin D derivatives, we demonstrated that VDR binding affinity does not directly correlate with neurogenic potential. These findings reveal distinct VDR-dependent and VDR-independent pathways in neural differentiation, highlighting a previously unrecognized role of vitamin D metabolism in neural fate determination. • CYP27B1 converts 25D 3 to 1α,25D 3 , which binds to VDR to promote neural stem cell differentiation. • Vitamin D derivatives studies show that VDR binding affinity isn't necessarily linked to neuronal differentiation. • Regardless of the presence or absence of CYP27B1, 25D 3 or 1α,25D 3 promotes astrocyte differentiation by binding to the VDR. • Vitamin D 1α,25D 3 promotes neuronal differentiation without involving the VDR, 25D 3 promotes astrocyte differentiation via the VDR.

Source: Biochemical and Biophysical Research Communications

DOI: 10.1016/j.bbrc.2025.151547