WNT5A is transported via lipoprotein particles in the cerebrospinal fluid to regulate hindbrain morphogenesis

WNTs are hydrophobic, lipid-modified proteins that control multiple functions in development and disease via short- and long-range signaling. However, it is unclear how these hydrophobic molecules reach over long distances in the mammalian brain. Here we show that WNT5A is produced by the choroid plexus (ChP) in the developing hindbrain, but not the telencephalon, in both mouse and human. Since the ChP produces and secretes the cerebrospinal fluid (CSF), we examined the presence of WNT5A in the CSF and found it is associated to lipoprotein particles rather than exosomes. Moreover, since the CSF flows along the surface of apical progenitors that do not express Wnt5a, we examined whether WNT5A up- or down-regulates their function. We found that Wnt5a down-regulates proliferation of such progenitor cells. Our study thus identifies the CSF as a route and lipoprotein particles as a vehicle for long-range transport of biologically active WNTs in the central nervous system.