Abstract
WNTs are 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 spread over long distances in the mammalian brain. Here we show that WNT5A is produced by the choroid plexus (ChP) of the developing hindbrain, but not the telencephalon, in both mouse and human. Since the ChP produces and secretes the cerebrospinal fluid (CSF), we examine the presence of WNT5A in the CSF and find that it is associated with lipoprotein particles rather than exosomes. Moreover, since the CSF flows along the apical surface of hindbrain progenitors not expressing Wnt5a, we examined whether deletion of Wnt5a in the ChP controls their function and find that cerebellar morphogenesis is impaired. Our study thus identifies the CSF as a route and lipoprotein particles as a vehicle for long-range transport of biologically active WNT in the central nervous system.
Highlights
WNTs are lipid-modified proteins that control multiple functions in development and disease via short- and long-range signaling
We demonstrate that WNT5A is produced in the epithelial cells of the hindbrain choroid plexus (HbChP) in a very specific temporal developmental window, from E12.5 to early postnatal age in mouse
Our results show that WNT5A colocalizes with lipoproteins in the apical part of both the HbChP epithelium, a cell type that expresses Wnt5a, and in target hindbrain progenitors lining the ventricle, that express Wnt proteins (Wnts) receptors, signaling components as well as receptors for lipoprotein particles, but do not express Wnt5a
Summary
WNTs are lipid-modified proteins that control multiple functions in development and disease via short- and long-range signaling It is unclear how these hydrophobic molecules spread over long distances in the mammalian brain. This study proposed a role of the ChP in regulation of WNT4 secretion into the CSF and WNT signaling at a distant site It is unclear whether WNT4 does really control proliferation in a direct manner at a site distant to where it is produced in vivo. Our result identifies WNT5A as a key regulator of morphogenic behavior of dorsal hindbrain progenitors near, but not adjacent, to the ChP and identify lipoprotein particles as the mechanism of transport of biologically active WNT proteins in the CSF
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