Di-rectifying Tau.

In this issue of The EMBO Journal, Li et al (2011) show that the axon initial segment (AIS) functions as a retrograde trafficking barrier, or axonal rectifier, to exclude axonal Tau from re-entry into the somatodendritic compartment. They elucidate the molecular basis of this rectification by showing that hyperphosphorylation of Tau permits it to detach from microtubules (MTs) and bypass the retrograde barrier. Neurons are highly polarized cells with distinct axo-dendritic polarity that is central to proper nervous system function. Polarity is reflected by the restricted localization of membrane and cytosolic proteins to dendritic or axonal compartments. For example, Map2 and Tau are MT-associated proteins (MAPs) that in mature neurons sort to somatodendritic or axonal compartments, respectively. What determines the selective localization and retention of these proteins within the axon, or within the dendrite? During early development, sorting of proteins to distinct domains can occur through multiple mechanisms. For example, direct and selective mobilization of cargoes by motor proteins such as kinesins or dyneins along MTs can restrict proteins to unique compartments (Hirokawa and Takemura, 2005). Proteins can also be stabilized, anchored, or tethered within specific compartments, or polarity may result from the assembly of molecular fences or physical barriers. In neurons, the AIS is an excellent example of a barrier that limits mixing of somatodendritic and axonal proteins, organelles, and even lipids (Rasband, 2010). The AIS is located at the base of the axon hillock and defines the transition from somatodendritic to axonal domains (Figure 1A). It is enriched with the cytoskeletal scaffolding proteins ankyrinG and bIV spectrin, which together cluster Naþ and Kþ channels and link them to the actin cytoskeleton (Figure 1B). These ion channel clusters initiate and modulate action potentials at the AIS, and function as a physiological bridge between somatodendritic input and axonal output. What do we know about the AIS barrier? The AIS barrier impedes the lateral mobility of membrane proteins in mature neurons and consists of detergent insoluble protein complexes (Winckler et al, 1999). The AIS barrier was also