Hypotheses concerning how Otx2 makes its incredible journey: a hitchhiker on the road to Rome?

INTRODUCTION From work carried out largely by Alain Prochiantz and his co-workers at the College de France (Sugiyama et al., 2008; Beurdeley et al., 2012; Carlier et al., 2013; Smythies and Edelstein, 2013; Spatazza et al., 2013a,b), it is now known that the homeoprotein and transcription factor molecule Otx2 possesses a very unusual property. This flexible molecule is able to cross cell membranes without using a specific energy-requiring carrier. The entry mechanism involves organizing a micelle structure out of the planar lipoprotein plasma membrane via interactions between charged residues and lipophilic interactions. This micelle carries the molecule of Otx2 across the membrane. It has been shown that the membrane exit mechanism of a related molecule, Engrailed 2, is different and involves the formation of energy-dependent calveolilike vesicles (Sugiyama et al., 2008; Carlier et al., 2013; Spatazza et al., 2013a). These vesicles are delivered into the interior of the cell. When injected into the eye Otx2 is transported to the visual cortex where it enters PV-expressing GABAergic INs (PVs), which it activates (Sugiyama et al., 2008; Beurdeley et al., 2012; Carlier et al., 2013; Spatazza et al., 2013a,b). During natural development, following the opening of the eyes, Otx2 molecules accumulate “gradually” in the visual cortex. In vivo, the molecule at source is synthesized in a retinal bipolar cell and transmitted to a retinal ganglion cell. The ganglion cell contains no Otx2 mRNA. At the other end of the journey, neither does the cortical cell; its Otx2 is transmitted from neurons in the lateral geniculate nucleus (LGN). AXONAL TRANSPORT Molecules are usually carried along axons by one of two mechanisms (Kaether et al., 2000; Roy, 2013). Individual proteins, bundled into packets called multiprotein complexes, are carried by the slow system. This moves at a speed of less than 0.8 cm a day. Vesicles, on the other hand, are carried by the fast system at speeds of up to 20 cm a day. The distance between the retina and the visual cortex in mice is about 1 cm. Thus a molecule taking the fast route could make the journey in about 1 h, whereas the minimum time for a molecule taking the slow route would be about 24 h—not allowing for the time needed to cross two synapses. The time that an Otx2 molecule takes to get from the retina to the cortex is 24 h (Prochiantz, personal communication). The rate of build-up would also depend on the amount of the molecule bring transmitted and the rate of diffusion at the target. Presumably, Otx2 would use one of these axonal transport mechanisms during its travel along axons, as it is difficult to visualize it wriggling on its own along axons from one cell to the next for these long distances.