Low-density lipoproteins from embryonic cerebrospinal fluid are required for neural differentiation

During development, embryonic cerebrospinal fluid(E-CSF) is involved in cell survival, proliferation, and neurogenesis of the neuroepithelial progenitor cells. We have recently identified a complex pattern of proteins in chick and rat E-CSF, which include apolipoproteins. Apolipoproteins play a critical role in the function of lipoproteins by interacting with receptors to deliver the lipid cargo to target cells. However, the function of these E-CSF apolipoproteins is unclear. Here, we characterized the chick E-CSF lipoprotein profile and analyzed the role of its lipoprotein fractions in neural differentiation. We found that the lipoprotein pattern of chick E-CSF differed significantly from that of adult plasma, with a major proportion of apoB-containing lipoproteins. Further, supplementation of lipoprotein-depleted fraction with E-CSF very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) resulted in 25% and 60%, respectively, of the neurogenesis induced by the whole E-CSF in chick neuroepithelium explants, whereas high-density lipoproteins caused the lowest induction. We further investigated the potential role of E-CSF LDL in vivo by analyzing neural differentiation in the neuroepithelium of wild-type (WT) and LDL receptor-knockout (LDLR KO) mouse embryos. E-CSF lipids were mainly associated with LDL in both WT and LDLR KO mice, and the latter exhibited a substantial increase in LDL lipids compared with WT mice. Externally, LDLR KO embryos were apparently normal, and they exhibited up to 26% reduction in the number of neural differentiating cells in comparison with WT mice, although this finding was not statistically significant. These data strongly suggest that E-CSF LDL plays a critical role during early neural differentiation.