Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. Here, we demonstrate that the protein kinase MST1 mediates oxidative-stress-induced cell death in primary mammalian neurons by directly activating the FOXO transcription factors. MST1 phosphorylates FOXO proteins at a conserved site within the forkhead domain that disrupts their interaction with 14-3-3 proteins, promotes FOXO nuclear translocation, and thereby induces cell death in neurons. We also extend the MST-FOXO signaling link to nematodes. Knockdown of the C. elegans MST1 ortholog CST-1 shortens life span and accelerates tissue aging, while overexpression of cst-1 promotes life span and delays aging. The cst-1-induced life-span extension occurs in a daf-16-dependent manner. The identification of the FOXO transcription factors as major and evolutionarily conserved targets of MST1 suggests that MST kinases play important roles in diverse biological processes including cellular responses to oxidative stress and longevity.

The development of the mammalian cerebellum is orchestrated by both cell-autonomous programs and inductive environmental influences. Here, we describe the main processes of cerebellar ontogenesis, highlighting the neurogenic strategies used by developing progenitors, the genetic programs involved in cell fate specification, the progressive changes of structural organization, and some of the better-known abnormalities associated with developmental disorders of the cerebellum.

The hereditary ataxias are a complex group of neurological disorders characterized by the degeneration of the cerebellum and its associated connections. The molecular mechanisms that trigger the loss of Purkinje cells in this group of diseases remain incompletely understood. Here, we report a previously undescribed dominant mouse model of cerebellar ataxia, moonwalker (Mwk), that displays motor and coordination defects and loss of cerebellar Purkinje cells. Mwk mice harbor a gain-of-function mutation (T635A) in the Trpc3 gene encoding the nonselective transient receptor potential cation channel, type C3 (TRPC3), resulting in altered TRPC3 channel gating. TRPC3 is highly expressed in Purkinje cells during the phase of dendritogenesis. Interestingly, growth and differentiation of Purkinje cell dendritic arbors are profoundly impaired in Mwk mice. Our findings define a previously unknown role for TRPC3 in both dendritic development and survival of Purkinje cells, and provide a unique mechanism underlying cerebellar ataxia.cerebellum ͉ dendritogenesis ͉ trp channel ͉ mouse mutant T he inherited cerebellar ataxias are a complex group of neurodegenerative disorders characterized by loss of balance and coordination (1-3). Cerebellar ataxia is caused by the degeneration of Purkinje cells, which form the sole output of the cerebellum. To date, more than 50 different inherited forms of cerebellar ataxia are known (4). Importantly, increasing evidence points to the existence of common pathological pathways in different forms of ataxia, including transcriptional regulation, protein aggregation, and calcium homeostasis, which trigger the degeneration of Purkinje cells in these disorders (1, 5). However, the molecular mechanisms mediating these pathways remain poorly understood.To identify gene products that might be key to cerebellar degeneration, we used a phenotype-driven approach to screen for ataxic behavior in a large cohort of N-ethyl-N-nitrosourea (ENU)-mutagenized mice (6). Here, we report that a point mutation (T635A) in the C3-type transient receptor potential (TRPC3) channel in the mouse results in Purkinje cell degeneration and cerebellar ataxia. We also find that the development of dendrites is severely impaired in mutant Purkinje cells. Notably, the identified dominant gain-of-function mutation in TRPC3 provides insight into the function of TRPC3 that powerfully complements the findings obtained from the recently published TRPC3 knockout mouse (7). Our findings suggest that TRPC3 is a regulator of development and survival of Purkinje cells, and link aberrant TRPC3 function to cerebellar disease.