Wnt and Hedgehog: Secretion of Lipid-Modified Morphogens

Morphogens are signaling molecules produced by a localized source, specifying cell fate in a graded manner. The source secretes morphogens into the extracellular milieu to activate various target genes in an autocrine or paracrine manner. Here we describe various secreted forms of two canonical morphogens, the lipid-anchored Hedgehog (Hh) and Wnts, indicating the involvement of multiple carriers in the transport of these morphogens. These different extracellular secreted forms are likely to have distinct functions. Here we evaluate newly identified mechanisms that morphogens use to traverse the required distance to activate discrete paracrine signaling. The membrane-anchored morphogens Hedgehog (Hh) and Wingless (Wg) play major roles in tissue patterning, tissue maintenance, and disease progression. Hh and Wg must be secreted for their paracrine signaling function. In addition to being secreted on exovesicles, Hh and Wg are found on circulating lipoproteins and decorating cytonemes as well as in soluble forms. The mechanism of Hh exovesicle generation involves its endocytosis from the cell surface regulated by Shibire (Drosophila dynamin) and Rab5-mediated endosomal progression, followed by sorting to intraluminal vesicles (ILVs) located in multivesicular bodies (MVBs) in an endosomal sorting complex required for transport (ESCRT)-dependent manner and subsequent release on exovesicles. In addition to the morphogens, exovesicles carry other targeting and regulatory molecules including cellular RNAs. Besides activating their direct downstream signaling targets, exosomes can deliver cargo that may influence the cell-fate decisions ascribed to these morphogens.