, 2013). Oh and Gu (2013) found that the secreted Semaphorin 3E (Sema3E) is expressed at the developing whisker follicle. Sema3E is an interesting candidate for patterning the double-ring structure because it has been shown in independent studies to shape vascular and neuronal networks. In the developing Proteases inhibitor whisker of Sema3e mutant embryos or embryos lacking its receptor Plexin D1, the stereotypical “nerve inside – vessel outside” pattern

was severely disrupted. Both nerves and vessels targeted and remodeled around whisker follicles, but the two ring structures appeared intermingled. Further analyses revealed that this phenotype was the effect of the inward displacement of the vascular ring, whereas the nerve ring remained essentially unaffected. Thus, expression of Sema3E at the whisker follicle provides a repulsive signal for Plexin D1-expressing endothelial

cells that is required to maintain the vascular ring in its outer position. The observed lack of effect of Sema3E/Plexin D1 signaling on the sensory innervation of the developing whisker was surprising, given the expression of the Plexin D1 receptor in trigeminal ganglion cells and the repulsive effect exerted by the Sema3E ligand on these same cells in vitro. Here, the authors describe a mechanism leading to neutralization of Sema3E inhibition in vivo. Using AT13387 a tagged Sema3E ligand as a probe to detect Plexin D1 expression, they showed that the receptor is heterogeneously distributed along the trigeminal axon pathway and is completely absent from the distalmost segments of the peripheral trigeminal branches. Not only may this local downregulation of Plexin D1 explain why nerve patterning occurs

normally in the absence of Sema3E/Plexin D1 signaling in vivo, but in a wild-type context it may also allow the nerve ring to maintain its inner position close to the source of the Sema3E repellent. If Sema3E does crotamiton not directly affect nerve patterning, then how are trigeminal axons initially directed to innervate the whisker follicle? The NGF/TrkA signaling system is a probable candidate for this innervation, given that NGF is expressed around the whisker follicle and its TrkA receptor is present all along innervating trigeminal axons. Previous research reported that peripheral sensory axons fail to properly innervate the whisker pads in mutants lacking trkA ( Patel et al., 2000). In this study, Oh and Gu (2013) further show that sensory axons extend normally along the trigeminal nerve in the absence of NGF, but that they fail to innervate the whisker pads and to form a well-organized nerve-ring structure.