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Although several molecules have been shown to play important roles in subtype specification of neocortical neurons, the entire mechanism involved in the specification, in particular, of upper cortical plate (UCP) neurons still remains unclear. The UCP, which is responsible for intracortical connections in the neocortex, comprises histologically, functionally, and molecularly different layer 2/3 (L2/3) and L4. Here, we report the essential interactions between two types of transcription factors, Rorb (RAR-related orphan receptor beta) and Brn1/2 (Brain-1/Brain-2), for UCP specification. We found that Brn2 expression was detected in all upper layers in the immature UCP, but was subsequently restricted to L2/3, accompanied by up-regulation of Rorb in L4, suggesting demarcation of L2/3 and L4 during cortical maturation. Rorb indeed inhibited Brn2 expression and the expression of other L2/3 characteristics, revealed by ectopic expression and knockdown studies. Moreover, this inhibition occurred through direct binding of Rorb to the Brn2 locus. Conversely, Brn1/2 also inhibited Rorb expression and the expression of several L4 characteristics. Together, these results suggest that a mutually repressive mechanism exists between Brn1/2 and Rorb expression and that the established expression of Brn1/2 and Rorb further specifies those neurons into L2/3 and L4, respectively, during UCP maturation.

Despite considerable scholarly attention on the institutional and normative aspects of development cooperation, its longitudinal dynamics unfolding at the global level have rarely been investigated. Focusing on aid, we examine the evolving global structure of development cooperation induced by aid flows in its entirety. Representing annual aid flows between donors and recipients from 1970 to 2013 as a series of networks, we apply hierarchical stochastic block models to extensive aid-flow data that cover not only the aid behavior of the major OECD donors but also that of other emerging donors, including China. Despite a considerable degree of external expansion and internal diversification of aid relations over the years, the analysis has uncovered a temporally persistent structure of aid networks. The latter comprises, on the one hand, a limited number of major donors with far-reaching resources and, on the other hand, a large number of mostly poor but globally well-connected recipients. The results cast doubt on the efficacy of recurrent efforts for “aid reform” in substantially changing the global aid flow pattern.

Neurons migrate a long radial distance by a process known as locomotion in the developing mammalian neocortex. During locomotion, immature neurons undergo saltatory movement along radial glia fibers. The molecular mechanisms that regulate the speed of locomotion are largely unknown. We now show that the serine/threonine kinase Akt and its activator phosphoinositide-dependent protein kinase 1 (PDK1) regulate the speed of locomotion of mouse neocortical neurons through the cortical plate. Inactivation of the PDK1–Akt pathway impaired the coordinated movement of the nucleus and centrosome, a microtubule-dependent process, during neuronal migration. Moreover, the PDK1–Akt pathway was found to control microtubules, likely by regulating the binding of accessory proteins including the dynactin subunit p150glued. Consistent with this notion, we found that PDK1 regulates the expression of cytoplasmic dynein intermediate chain and light intermediate chain at a posttranscriptional level in the developing neocortex. Our results thus reveal an essential role for the PDK1–Akt pathway in the regulation of a key step of neuronal migration.

Many cell-intrinsic mechanisms have been shown to regulate neuronal subtype specification in the mammalian neocortex. However, how much cell environment is crucial for subtype determination still remained unclear. Here, we show that knockdown of Protocadherin20 (Pcdh20), which is expressed in post-migratory neurons of layer 4 (L4) lineage, caused the cells to localize in L2/3. The ectopically positioned “future L4 neurons” lost their L4 characteristics but acquired L2/3 characteristics. Knockdown of a cytoskeletal protein in the future L4 neurons, which caused random disruption of positioning, also showed that those accidentally located in L4 acquired the L4 characteristics. Moreover, restoration of positioning of the Pcdh20-knockdown neurons into L4 rescued the specification failure. We further suggest that the thalamocortical axons provide a positional cue to specify L4 identity. These results suggest that the L4 identity is not completely determined at the time of birth but ensured by the surrounding environment after appropriate positioning. The outer surface of the brain (the neocortex) in mammals is formed out of neurons arranged into layers. These layers are laid down during embryonic development, and each layer has characteristic mix of distinct subtypes of neurons that have different forms and sizes. Previous evidence suggests that neurons that are born at around the same time end up in the same layer of the cortex, and tend to have the same form. It is also possible that the environment a newborn neuron finds itself in influences its eventual form. However, many previous studies have investigated the function of molecules that work within the neurons, and the effect that a neuron’s surroundings have on its development still remains largely unknown. Neurons that contain a protein called protocadherin20 normally end up in layer 4 of the neocortex. Oishi et al. genetically engineered mouse embryos so that the production of protocadherin20 was reduced in these neurons whilst the neocortex formed. These neurons were also tagged with a fluorescent marker, so that their eventual position and shape in the brain could be tracked. Examining the brains of the mice after they had been born showed that the tagged neurons ended up not in layer 4, but in layers 2 and 3 of the neocortex. What is more, these neurons now looked similar to other neurons in layer 2 and 3, as well as producing proteins and establishing connections consistent with their new location. However, further experiments that placed neurons with reduced levels of the protocadherin20 protein into layer 4 showed that these neurons acquire the characteristics of other layer 4 neurons, despite lacking a key layer 4 protein. These results therefore suggest that the eventual form of a neuron is not determined just by when it is born, but also by the environment that it finds itself in. In future studies, it will be important to clarify the molecular mechanism that provides the appropriate environment and so regulates the identity of the neurons in the developing cortex.

Neuronal subtypes in the mammalian cerebral cortex are determined by both intrinsic and extrinsic mechanisms during development. However, the extrinsic cues that are involved in this process remain largely unknown. Here, we investigated the role of sonic hedgehog (Shh) in glutamatergic cortical subtype specification. We found that E14.5-born, but not E15.5-born, neurons with elevated Shh expression frequently differentiated into layer 4 subtypes as judged by the cell positioning and molecular identity. We further found that this effect was achieved indirectly through the regulation of cell positioning rather than the direct activation of layer 4 differentiation programs. Together, we provided evidence that Shh, an extrinsic factor, plays an important role in the specification of cortical superficial layer subtypes.

This study investigates the effect of the α/C14 interface on the creep strength of α-Mg/C14–Mg2Ca eutectic alloy at 473 K under a stress of 40 MPa. The α/C14 interface is composed of terraces and steps, with terraces parallel to the (1101)α pyramidal plane of the α-Mg lamellae and to the (1120)C14 columnar plane of the C14–Mg2Ca lamellae. The creep curves of the alloy exhibit three stages: a normal transient creep stage, a minimum creep rate stage, and an accelerating stage. The minimum creep rate is proportional to the lamellar spacing, indicating that the α/C14 lamellar interface plays a creep-strengthening role. In the high-resolution transmission electron microscopy image captured of the specimen after the creep test, dislocations can be mainly seen within the soft α-Mg lamellae, and they are randomly distributed at the α/C14 interface. In contrast, dislocations are rarely introduced in the hard C14–Mg2Ca lamellae. It is deduced that the α/C14 interface presents a barrier to dislocation gliding within the α-Mg lamellae and does not help rearrange the dislocations.

Extracellular stimuli regulate neuronal differentiation and subtype specification during brain development, although the intracellular signaling pathways that mediate these processes remain largely unclear. We now show that the PDK1-Akt pathway regulates differentiation of telencephalic neural precursor cells (NPCs). Active Akt promotes differentiation of NPC into γ-aminobutyric acid-containing (GABAergic) but not glutamatergic neurons. Disruption of the Pdk1 gene or expression of dominant-negative forms of Akt suppresses insulin-like growth factor (IGF)-1 enhancement of NPC differentiation into neurons in vitro and production of neocortical GABAergic neurons in vivo. Furthermore, active Akt increased the protein levels and transactivation activity of Mash1, a proneural basic helix-loop-helix protein required for the generation of neocortical GABAergic neurons, and Mash1 was required for Akt-induced neuronal differentiation. These results have unveiled an unexpected role of the PDK1-Akt pathway: a key mediator of extracellular signals regulating the production of neocortical GABAergic neurons.

Numerous studies have investigated the formation of interhemispheric connections which are involved in high-ordered functions of the cerebral cortex in eutherian animals, including humans. The development of callosal axons, which transfer and integrate information between the right/left hemispheres and represent the most prominent commissural system, must be strictly regulated. From the beginning of their growth, until reaching their targets in the contralateral cortex, the callosal axons are guided mainly by two environmental cues: (1) the midline structures and (2) neighboring? axons. Recent studies have shown the importance of axona guidance by such cues and the underlying molecular mechanisms. In this paper, we review these guidance mechanisms during the development of the callosal neurons. Midline populations express and secrete guidance molecules, and “pioneer” axons as well as interactions between the medial and lateral axons are also involved in the axon pathfinding of the callosal neurons. Finally, we describe callosal dysgenesis in humans and mice, that results from a disruption of these navigational mechanisms.

The diversification of neuronal subtypes during corticogenesis is fundamental to the establishment of the complex cortical structure. Although subtype specification has been assumed to occur in neural progenitor cells, increasing evidence has begun to reveal the plasticity of subtype determination in immature neurons. Here, we summarize recent findings regarding the regulation of subtype specification during later periods of neuronal differentiation, such as the post-mitotic and post-migratory stages. We also discuss thalamocortical axons as an extra-cortical cue that provides information on the subtype determination of immature cortical neurons.

Measurements of reaction rates by secondary neutrons produced from beam losses by 17-MeV protons are conducted at a compact cyclotron facility with the foil activation method. The experimentally obtained distribution of the reaction rates of 197Au (n, γ) 198Au on the concrete walls suggests that a target and an electrostatic deflector as machine components for beam extraction of the compact cyclotron are principal beam loss points. The measurements are compared with calculations by the Monte Carlo code: PHITS. The calculated results based on the beam losses are good agreements with the measured ones within 21%. In this compact cyclotron facility, exponential attenuations with the distance from the electrostatic deflector in the distributions of the measured reaction rates were observed, which was looser than that by the inverse square of distance.