The once-neglected p75 neurotrophin receptor (p75NTR) has been getting a lot of attention lately – and rightly so, given its diverse signaling roles and its function as the cell death counterpart to the well studied Trk neurotrophin receptors, which promote cell survival. Dechant and colleagues from the Max Planck Institute of Neurobiology in Martinsried continue this trend on page 977 of this issue by showing that a recently identified, short splice variant of p75NTR is critical to development not only of the nervous system but also of the vascular system. The authors made a transgenic mouse that lacks both the full length p75NTR receptor and the short variant (which was still expressed in the initial knockout of this receptor). This new mutant has a number of phenotypic characteristics presumably specific to the loss of the short splice variant. In addition to more severe defects in motility and peripheral nerve morphology than the long splice variant knockout, the newly characterized mutants are smaller than their wild-type counterparts (pictured). The mutants also have increased lethality at birth, most likely due to the vascular defects. The short p75NTR protein has an intact intracellular signaling domain, but lacks an extracellular neurotrophin binding domain. Because the mechanism of the short isoform's signaling is not well understood, clues to its function from the knockout may be particularly important.