This paper estimates 50-year trends in the intergenerational persistence of educational attainment for a sample of 42 nations around the globe. Large regional differences in educational persistence are documented, with Latin America displaying the highest intergenerational correlations, and the Nordic countries the lowest. We also demonstrate that the global average correlation between parent and child's schooling has held steady at about 0.4 for the past fifty years.

Most cases of early-onset torsion dystonia are caused by deletion of GAG in the coding region of the DYT1 gene encoding torsinA. This autosomal dominant neurologic disorder is characterized by abnormal movements, believed to originate from neuronal dysfunction in the basal ganglia of the human brain. The torsins (torsinA and torsinB) are members of the "ATPases associated with a variety of cellular activities" (AAA(+)) superfamily of proteins that mediate chaperone and other functions involved in conformational modeling of proteins, protection from stress, and targeting of proteins to cellular organelles. In this study, the intracellular localization and levels of endogenous torsin were evaluated in rat pheochromocytoma PC12 cells following differentiation and stress. TorsinA, apparent MW 37 kDa, cofractionates with markers for the microsomal/endoplasmic reticulum (ER) compartment and appears to reside primarily within the ER lumen based on protease resistance. TorsinA immunoreactivity colocalizes with the lumenal ER protein protein disulfide isomerase (PDI) and extends throughout neurites. Levels of torsinA did not increase notably in response to nerve growth factor-induced differentiation. None of the stress conditions tested, including heat shock and the unfolded protein response, affected torsinA, except for oxidative stress, which resulted in an increase in the apparent MW of torsinA and redistribution to protrusions from the cell surface. These findings are consistent with a relatively rapid covalent modification of torsinA in response to oxidative stress causing a change in state. Mutant torsinA may interfere with and/or compromise ER functions, especially in dopaminergic neurons, which have high levels of torsinA and are intrinsically vulnerable to oxidative stress.

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The WASP and cortactin families constitute two distinct classes of Arp2/3 modulators in mammalian cells. Physical and functional interactions among the Arp2/3 complex, VCA (a functional domain of N-WASP), and cortactin were examined under conditions that were with or without actin polymerization. In the absence of actin, cortactin binds significantly weaker to the Arp2/3 complex than VCA. At concentrations of VCA 20-fold lower than cortactin, the association of cortactin with the Arp2/3 complex was nearly abolished. Analysis of the cells infected with Shigella demonstrated that N-WASP located at the tip of the bacterium, whereas cortactin accumulated in the comet tail. Interestingly, cortactin promotes Arp2/3 complex-mediated actin polymerization and actin branching in the presence of VCA at a saturating concentration, and cortactin acquired 20 nM affinity for the Arp2/3 complex during actin polymerization. The interaction of VCA with the Arp2/3 complex was reduced in the presence of both cortactin and actin. Moreover, VCA reduced its affinity for Arp2/3 complex at branching sites that were stabilized by phalloidin. These data imply a novel mechanism for the de novo assembly of a branched actin network that involves a coordinated sequential interaction of N-WASP and cortactin with the Arp2/3 complex.

Separation of clathrin-coated pits from the plasma membrane, a key event during endocytosis, is thought to be driven by dynamin and the actin cytoskeleton. However, the mechanism for the actin-mediated endocytosis remains elusive. RNA interference-mediated suppression of cortactin, an F-actin binding protein that promotes Arp2/3 complex-mediated actin polymerization, effectively blocked transferrin uptake. Depletion of cortactin in brain cytosol inhibited formation of clathrin-coated vesicles by 70% as analyzed in a cell-free system. Interestingly, the interaction between cortactin and dynamin 2 in cells was dependent on actin polymerization and was attenuated upon cell exposure to cytochalasin D as analyzed by immunofluorescence and immunoprecipitation. Moreover, a cortactin mutant deficient in Arp2/3 binding colocalized less efficiently with dynamin 2 and inhibited the uptake of transferrin. The effect of actin polymerization on the interaction between cortactin and the dynamin proline-rich domain (PRD) was further evaluated under a condition for actin polymerization in vitro. Cortactin binds to the dynamin PRD with an equilibrium dissociation constant of 81 nM in the presence of the Arp2/3 complex and actin, and 617 nM in the absence of actin polymerization. Taken together, these data demonstrate that Arp2/3-mediated actin polymerization regulates the accessibility of cortactin to dynamin 2 and imply a novel mechanism by which cortactin and dynamin drive the fission of clathrin-coated pits in an actin polymerization dependent manner.

Tuberous sclerosis complex (TSC)1 is an autosomal dominant disorder characterized by benign hamartomas in brain, kidney, heart, lung, and skin. It is a developmental disorder with abnormalities in cell migration, differentiation, and proliferation. Neurological complications include seizures, mental retardation, and autism (1). The disease is caused by mutations in tumor suppressor genes TSC1 or TSC2 encoding hamartin and tuberin, respectively (2, 3). Hamartin and tuberin associate in vivo forming a complex with other proteins (4). Rodent models of Tsc1 and Tsc2 develop renal cyst adenomas with liver hemangiomas observed in mouse models (5-8). Mutations in either Drosophila Tsc1 or Tsc2 show increase in cell and organ size, whereas co-expression of dTsc1 and dTsc2 inhibits growth and reduces cell size (9 -12). Studies from fly also suggest that dS6 kinase may be an inhibitory target of dTsc1 and dTsc2 in growth control (10 -12). Recent studies have confirmed that mammalian TSC1 and TSC2 inhibit S6 kinase (S6K). Cells harboring mutations in either TSC1 or TSC2 have constitutively high phosphorylation of both S6K and its substrate S6 (8, 13-18). Furthermore, tuberin and hamartin function together to inhibit target of rapamycin-mediated signaling to S6K in mammals as well as in fly (15,16,18,19). Akt phosphorylates tuberin and inhibits tuberin-hamartin function (14,16,20,21). Furthermore, it is evident from the most recent reports that the small GTPase Rheb is a direct target of tuberin and hamartin in both the Drosophila and mammalian systems (22)(23)(24). These studies demonstrate Rheb GTPase-activating protein activity for tuberin, and the loss of tuberin and/or hamartin lead to an increase in GTP-bound Rheb, which in turn leads to activation of the mammalian target of rapamycin/S6K/4E-binding protein signaling pathway.Thus, recent studies have placed tuberin and hamartin in growth signaling pathways; however, critical CNS functions of these proteins remain unknown. Our recent work demonstrates that unlike kidney lesions, CNS lesions such as cortical tubers do not display a second somatic mutation and other mechanisms might play a role during tumorigenesis in the CNS (25). Furthermore, we have shown that the tuberinhamartin complex exists with neurofilament light chain and ezrin, radixin, and moesin (ERM) proteins in the growth cone and could play a role in neuronal migration (26). In our efforts to understand the tuberin-hamartin complex in the CNS, we have identified Pam (protein-associated with Myc) (27) as a physiologically relevant tuberin interactor and have shown that Pam exists in complex with tuberin-hamartin in the CNS. Our results also demonstrate that HIW, the Drosophila homolog of Pam, can genetically interact with dTsc1-dTsc2 in the fly. The evidence that the Pam homologs in worm (RPM-1) (28, 29) and in Drosophila (HIW) (30) are important regulators of synaptic growth suggests that the interaction of Pam with tuberin-hamartin will be highly relevant within the CNS. EXPERIMENTAL PROCEDUREScDNA Const...

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Neurofibromatosis 2 (NF2) is a dominantly inherited disorder characterized by bilateral vestibular schwannomas and meningiomas. Merlin, the neurofibromatosis 2 tumor suppressor protein, is related to the ERM (ezrin, radixin, moesin) proteins and, like its family members, is thought to play a role in plasma membrane-cytoskeletal interactions. We report a novel protein as a merlin-specific binding partner that we have named magicin (merlin and Grb2 interacting cytoskeletal protein) and show that the two proteins interact in vitro and in vivo as well as colocalize beneath the plasma membrane. Magicin is a 24 kDa protein that is expressed in many cell lines and tissues. Magicin, similar to merlin, associates with the actin cytoskeleton as determined by cofractionation, immunofluorescence and electron microscopy. Analysis of the magicin sequence reveals binding motifs for the adaptor protein Grb2. Employing affinity binding, blot overlay and co-immunoprecipitation assays, we demonstrate an interaction between Grb2 and magicin. In addition, merlin is capable of forming a ternary complex with magicin and Grb2. These results support a role for merlin in receptor-mediated signaling at the cell surface, and may have implications in the regulation of cytoskeletal reorganization.