Klotho exerts anti-aging properties in mammals in two different ways. While membrane-bound Klotho, which is primarily expressed in the kidney, acts as an obligate co-receptor of FGF23 to regulate phosphate homeostasis, secreted Klotho, resulting from the shedding of the KL1-KL2 ectodomain into the bloodstream, inhibits Insulin/IGF1 signalling. However, the underlying molecular mechanisms are not fully understood. Here, we investigated the biological role of Klotho in Caenorhabditis elegans. Two redundant homologues of the klotho gene exist in C. elegans and encode predicted proteins homologous to the  glucosidase-like KL1 domain of mammalian Klotho. We have used a genetic approach to investigate the functional activity of Klotho in C. elegans. Here, we report that whereas Klotho requires EGL-15 (FGFR) and EGL-17 to promote longevity and oxidative stress resistance, it is not involved in the regulation of fluid homeostasis, controlled by LET-756. Besides revealing a new post-developmental role for EGL-17, our data suggest that the KL1 form of Klotho is involved in FGF23-independent FGF signalling. We also report a genetic interaction between Klotho and the DAF-2 (Ins/IGF1R)/DAF-16 (FOXO) pathway. While the regulation of longevity requires functional DAF-2/DAF-16 signalling, the control of oxidative stress resistance involves a DAF-2- independent, DAF-16-dependent pathway, suggesting that Klotho may target either DAF-2 or DAF-16, depending of environmental conditions. Thus, the predictive KL1 form of Klotho appears to crosstalk with both FGF and Insulin/IGF1/FOXO pathways to exert anti-aging properties in C. elegans.

During sustained depolarization, voltage-gated Ca²⁺ channels progressively undergo a transition to a nonconducting, inactivated state, preventing Ca²⁺ overload of the cell. This transition can be triggered either by the membrane potential (voltage-dependent inactivation) or by the consecutive entry of Ca²⁺(Ca²⁺-dependent inactivation), depending on the type of Ca²⁺ channel. These two types of inactivation are suspected to arise from distinct underlying mechanisms, relying on specific molecular sequences of the different pore-forming Ca²⁺ channel subunits. Here we report that the voltage-dependent inactivation (of the α_1ACa²⁺ channel) and the Ca²⁺-dependent inactivation (of the α_1C Ca²⁺ channel) are similarly influenced by Ca²⁺ channel β subunits. The same molecular determinants of the β subunit, and therefore the same subunit interactions, influence both types of inactivation. These results strongly suggest that the voltage and the Ca²⁺-dependent transitions leading to channel inactivation use homologous structures of the different α₁ subunits and occur through the same molecular process. A model of inactivation taking into account these new data is presented.

The Aurora kinase family has been involved bothin vivo and in vitro in the stability of the metaphase plate and chromosome segregation. However, to date only one member of this family, the protein kinase Aurora B, has been implicated in the regulation of meiotic division inCaenorhabditis elegans. In this species, disruption of Aurora B results in the failure of polar body extrusion. To investigate whether Aurora A is also required in meiosis, we microinjected highly specific α-Aurora A antibodies in Xenopus oocytes. We demonstrated that microinjected oocytes fail to extrude the first polar body and are arrested with condensed chromosomes on a typical metaphase I plate, which has not performed its normal 90° rotation. We additionally found that, although the failure of first polar body extrusion observed in α-Aurora A-microinjected oocytes is likely mediated by Eg5, the impairment of the metaphase plate rotation does not involve this kinesin-like protein. Surprisingly, although chromosomes remain condensed at a metaphase I stage in α-Aurora A-microinjected oocytes, the cytoplasmic cell cycle events progress normally through meiosis until metaphase II arrest. Moreover, these oocytes are able to undergo parthenogenetic activation. We conclude that Aurora A and Eg5 are involved in meiosis I to meiosis II transition in Xenopus oocytes.