A GTPase that goes both ways

Survival gets more complicated NTF and related proteins have been shown to promote the survival of motoneurons in two different settings: during embryonic development and after nerve injury in adults. Because the signal and the response are apparently the same in the two situations, a simple explanation is that embryonic and adult neurons use the same signaling pathways to promote survival. But on page 287, Schweizer et al. show that the simplest hypothesis is not always the correct one. Earlier work had shown that CNTF activates the LIF receptor to promote neuronal survival, and that Stat-3 is an important downstream effector of the LIF receptor. The authors used Cre-mediated recombination in a transgenic mouse system to delete the Stat-3 gene in neurons of the facial nucleus and spinal cord. Surprisingly, the mice develop normally, with no neuronal defects. When the facial nerves of adult mice are damaged, however, they show a dramatic loss of motoneurons compared with wild-type controls. Therefore, Stat-3–mediated signaling appears to be essential for motoneuron survival after injury, but dispensible during embryonic development, suggesting that neurons use different pathways at different times to transduce the same signal. ᭿ C Motoneurons are lost in injured mice lacking Stat-3 (top) relative to wild type (bottom). A GTPase that goes both ways ellular GTPases are generally placed into one of two categories: signaling switches such as the onco-gene ras or assembly factors such as the translation elongation factor EF-Tu (EF-1a in eukaryotes). But on page 315, Gladfelter et al. show that yeast Cdc42p, a well-characterized ras-like switch, can also behave as an EF-Tu–like assembly factor. The work is the first description of a GTPase changing hats in this way, and it suggests that GTPases may defy strict categorization. Like all ras-like GTPases, Cdc42p activates downstream effectors when bound to GTP, and stops signaling after it hydrolyzes the GTP to GDP. In an effort to study Cdc42p activity during the assembly of the septin ring, a structure important in yeast budding, the authors characterized two cdc42 mutants with defects in septin ring assembly. Surprisingly, both of the recessive mutants exhibited reduced GTP hydrolysis, and overexpression of a Cdc42p GTPase activating protein could overcome their septin ring defects. If Cdc42p acted only as a ras-like GTPase, mutations that reduce GTP hydrolysis should lead to constitutive signaling and be dominant. The authors propose that, in addition to its ras-like signaling capabilities, Cdc42p can …