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.

Cortical development depends on the active integration of cell autonomous and extrinsic cues, but the coordination of these processes is poorly understood. Here, we show that the apical complex protein Pals1 and Pten have opposing roles in localizing the Igf1R to the apical, ventricular domain of cerebral cortical progenitor cells. We found that the cerebrospinal fluid (CSF), which contacts this apical domain, has an age-dependent effect on proliferation, much of which is attributable to Igf2, but that CSF contains other signaling activities as well. CSF samples from patients with glioblastoma multiforme show elevated Igf2 and stimulate stem cell proliferation in an Igf2-dependent manner. Together, our findings demonstrate that the apical complex couples intrinsic and extrinsic signaling, enabling progenitors to sense and respond appropriately to diffusible CSF-borne signals distributed widely throughout the brain. The temporal control of CSF composition may have critical relevance to normal development and neuropathological conditions.

Summary Hemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged, malformed cerebral hemisphere, typically causing epilepsy that requires surgical resection. We studied resected HMG tissue to test whether the condition might reflect somatic mutations affecting genes critical to brain development. We found that 2/8 HMG samples showed trisomy of chromosome 1q, encompassing many genes, including AKT3, which is known to regulate brain size. A third case showed a known activating mutation in AKT3 (c.49G→A, creating p.E17K) that was not present in the patient’s blood cells. Remarkably, the E17K mutation in AKT3 is exactly paralogous to E17K mutations in AKT1 and AKT2 recently discovered in somatic overgrowth syndromes. We show that AKT3 is the most abundant AKT paralogue in brain during neurogenesis and that phosphorylated AKT is abundant in cortical progenitor cells. Our data suggest that somatic mutations limited to brain could represent an important cause of complex neurogenetic disease.

The choroid plexus (ChP) is the principal source of cerebrospinal fluid (CSF), which has accepted roles as a fluid cushion and a sink for nervous system waste in vertebrates. Various animal models have provided insight into how the ChP–CSF system develops and matures. In addition, recent studies have uncovered new, active roles for this dynamic system in the regulation of neural stem cells, critical periods and the overall health of the nervous system. Together, these findings have brought about a paradigm shift in our understanding of brain development and health, and have stimulated new initiatives for the treatment of neurological disease.

A mechanism that triggers neuronal apoptosis has been characterized. We report that the cell cycle-regulated protein kinase Cdc2 is expressed in postmitotic granule neurons of the developing rat cerebellum and that Cdc2 mediates apoptosis of cerebellar granule neurons upon the suppression of neuronal activity. Cdc2 catalyzes the phosphorylation of the BH3-only protein BAD at a distinct site, serine 128, and thereby induces BAD-mediated apoptosis in primary neurons by opposing growth factor inhibition of the apoptotic effect of BAD. The phosphorylation of BAD serine 128 inhibits the interaction of growth factor-induced serine 136-phosphorylated BAD with 14-3-3 proteins. Our results suggest that a critical component of the cell cycle couples an apoptotic signal to the cell death machinery via a phosphorylation-dependent mechanism that may generally modulate protein-protein interactions.

Highlights d Distinct pathophysiologies cause peripheral sensory neuron dysfunction in ASD models d Peripheral somatosensory neuron dysfunction alters brain development and behavior d A peripherally restricted GABA A R agonist, isoguvacine, reduces tactile sensitivity d Chronic isoguvacine treatment improves a subset of ASDrelated phenotypes in mice

Cerebral cortical progenitor cells can be classified into several different types, and each progenitor type integrates cell-intrinsic and cell-extrinsic cues to regulate neurogenesis. On one hand, cell-intrinsic mechanisms that depend upon appropriate apical-basal polarity are established by adherens junctions and apical complex proteins and are particularly important in progenitors with apical processes contacting the lateral ventricle. The apical protein complexes themselves are con-centrated at the ventricular surface, and apical complex proteins regulate mitotic spindle orientation and cell fate. On the other hand, remarkably little is known about how cell-extrinsic cues signal to progenitors and couple with cell-intrinsic mechanisms to instruct neurogenesis. Recent research shows that the cerebrospinal fluid, which contacts apical progenitors at the ventricular surface and bathes the apical complex of these cells, provides growth- and survival-promoting cues for neural progenitor cells in developing and adult brain. This review addresses how the apical-basal polarity of progenitor cells regulates cell fate and allows progenitors to sample diffusible signals distributed by the cere-brospinal fluid. We also review several classes of signaling factors that the cerebrospinal fluid distributes to the developing brain to instruct neurogenesis.

The protein kinase mammalian Sterile 20-like kinase 1 (MST1) plays a critical role in the regulation of cell death. Recent studies suggest that MST1 mediates oxidative stress-induced neuronal cell death by phosphorylating the transcription factor FOXO3 at serine 207, a site that is conserved in other FOXO family members. Here, we show that MST1-induced phosphorylation of FOXO1 at serine 212, corresponding to serine 207 in FOXO3, disrupts the association of FOXO1 with 14-3-3 proteins. Accordingly, MST1 mediates the nuclear translocation of FOXO1 in primary rat cerebellar granule neurons that are deprived of neuronal activity. We also find a requirement for MST1 in cell death of granule neurons upon withdrawal of growth factors and neuronal activity, and MST1 induces cell death in a FOXO1-dependent manner. Finally, we show that the MST1-regulatory, scaffold protein Nore1 is required for survival factor deprivation induced neuronal death. Collectively, these findings define MST1-FOXO1 signaling as an important link survival factor deprivation-induced neuronal cell death with implications for our understanding of brain development and neurological diseases.During normal development, neurons die by the process of apoptosis to ensure the proper wiring of the nervous system (1, 2). In the mature nervous system, aberrant neuronal cell death contributes to the pathogenesis of a large number of diseases (3-5). Therefore, elucidation of the molecular underpinnings of neuronal cell death is essential for our understanding of brain development and also offers the possibility of identification of targets for the development of drugs that prevent neuronal degeneration in brain diseases.Granule neurons of the rat cerebellum provide a robust system for the study of the mechanisms that govern neuronal cell death (6, 7). The survival of cerebellar granule neurons during normal development is promoted by growth factors and neuronal activity (8 -12). Likewise, the survival of primary rat cerebellar granule neurons is supported by polypeptide growth factors, provided by serum and neuronal activity, and mimicked by the activation of voltage-sensitive calcium channels induced by membrane depolarization (13-15). Granule neurons have also proved useful in the study of mechanisms of neuronal cell death in response to pathologically relevant stimuli such as oxidative stress (16).The protein kinase mammalian Sterile 20-like kinase 1 (MST1) 5 has been implicated in the control of neuronal cell death (16,17). Exposure of rat cerebellar granule neurons to hydrogen peroxide leads to MST1-dependent cell death (16). Oxidative stress-induced MST1 triggers neuronal cell death via the transcription factor FOXO3. MST1 catalyzes the phosphorylation of FOXO3 at serine 207, a site that lies within its forkhead domain, and thereby promotes the dissociation of FOXO3 from 14-3-3 proteins. The 14-3-3 proteins sequester FOXO3 in the cytoplasm and thus inhibit FOXO3-dependent transcription and cell death. The consequence of the MST1-induced phosphorylation of...