RhoGEF Trio Regulates Radial Migration of Projection Neurons via Its Distinct Domains

The radial migration of cortical pyramidal neurons (PNs) during corticogenesis is necessary for establishing a multilayered cerebral cortex. Neuronal migration defects are considered a critical etiology of neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia, epilepsy, and intellectual disability (ID). TRIO is a high-risk candidate gene for ASDs and ID. However, its role in embryonic radial migration and the etiology of ASDs and ID are not fully understood. In this study, we found that the in vivo conditional knockout or in utero knockout of Trio in excitatory precursors in the neocortex caused aberrant polarity and halted the migration of late-born PNs. Further investigation of the underlying mechanism revealed that the interaction of the Trio N-terminal SH3 domain with Myosin X mediated the adherence of migrating neurons to radial glial fibers through regulating the membrane location of neuronal cadherin (N-cadherin). Also, independent or synergistic overexpression of RAC1 and RHOA showed different phenotypic recoveries of the abnormal neuronal migration by affecting the morphological transition and/or the glial fiber-dependent locomotion. Taken together, our findings clarify a novel mechanism of Trio in regulating N-cadherin cell surface expression via the interaction of Myosin X with its N-terminal SH3 domain. These results suggest the vital roles of the guanine nucleotide exchange factor 1 (GEF1) and GEF2 domains in regulating radial migration by activating their Rho GTPase effectors in both distinct and cooperative manners, which might be associated with the abnormal phenotypes in neurodevelopmental disorders.

The Flattening Metallicity Gradient in the Milky Way’s Thin Disk

We calculate the ages, orbits and phase-space coordinates for a sample of ∼4 million LAMOST and Gaia stars. The ages are cross-matched and compared with values from two other popular age catalogs, which derive the ages using different methods. Of these ∼4 million stars, we select a sample of 1.3 million stars and investigate their radial metallicity gradients (as determined by orbital radii) as a function of their ages. This analysis is performed on various subsets of the data split by chemistry and orbital parameters. We find that commonly used selections for “thin disk” stars (such as low-α chemistry or vertically thin orbits) yield radial metallicity gradients that generally grow shallower for the oldest stars. We interpret this as a hallmark feature of radial migration (churning). Constraining our sample to very small orbital Z max (the maximal height of a star’s integrated orbit) makes this trend most pronounced. A chemistry-based “thin disk” selection of α-poor stars displays the same trend, but to a lesser extent. Intriguingly, we find that “thick disk” selections in chemistry and Z max reveal slightly positive radial metallicity gradients, which seem similar in magnitude at all ages. This may imply that the thick disk population is well mixed in age, but not in radius. This finding could help constrain conditions during the early epochs of Milky Way formation and shed light on processes such as the accretion and reaccretion of gases of different metallicities.

Periodic Unsteady Kinematics of Hub Flows in a Shrouded Multistage Compressor

Periodic unsteady flow kinematics in a shrouded multistage low-speed axial compressor has been measured for the first time. Data have been acquired at the inlet and exit of a shrouded 3rd- stage stator with a particular focus on the hub flows. The newly found features of the hub flow in a shrouded multistage compressor are different from those at the midspan or in unshrouded (i.e., cantilevered) compressors. First, the merging of the 2nd-stage stator and 3rd-stage rotor wakes causes positive radial migration near the rotor wake pressure surface at the hub of the 3rd-stage stator inlet. Second, the low-momentum labyrinth seal leakage flow of the 3rd-stage stator merges with the 3rd-stage rotor wake to create streamwise vorticity at the 3rd-stage stator inlet hub. Third, contrary to unshrouded stators, suction side hub corner separation in the shrouded 3rd-stage stator reduces rotor wake stretching. Thus, velocity disturbances are attenuated less, and amplitudes of periodic fluctuations in flow angles are larger at the 3rd-stage stator exit hub than at midspan. The positive radial migration of the rotor wake hub flow and wake stretching reduction are expected to decrease efficiency, whereas streamwise vorticity generation is expected to increase efficiency.

Behavioral Symptoms May Correlate With the Load and Spatial Location of Tubers and With Radial Migration Lines in Tuberous Sclerosis Complex

Objective: Tuberous sclerosis complex (TSC) is a multisystem neurocutaneous genetic disorder. The clinical manifestations are extensive and include neurological, dermatological, cardiac, ophthalmic, nephrological, and neuropsychiatric manifestations. The prediction and pathophysiology of neuropsychiatric disorders such as emotional symptoms, conduct problems, hyperactivity, and poor social behavior are poorly understood. The aim of the study was to diagnose neuropsychiatric symptoms in individuals with TSC, and to examine their possible correlations with quantity, magnitude, and spatial location of tubers and radial migration (RM) lines.Methods: The cohort comprised 16 individuals with TSC, aged 5–29 years, with normal or low normal intelligence. The participants or their parents were requested to fill Strengths and Difficulties Questionnaire (SDQ) and the TAND (TSC-associated neuropsychiatric disorders) Checklist for assessment of their neuropsychiatric symptoms. Correlations were examined between these symptoms and the magnitude, quantities, and locations of tubers and white matter RM lines, as identified in T2/FLAIR brain MRI scans.Results: The SDQ score for peer relationship problems showed correlation with the tuber load (r = 0.52, p < 0.05). Tuber load and learning difficulties correlated significantly in the temporal and parietal area. Mood swings correlated with tubers in the parietal area (r = 0.529, p < 0.05). RM lines in the temporal area correlated with abnormal total SDQ (r = 0.51, p < 0.05). Anxiety and extreme shyness were correlated with RM lines in the parietal area, r = 0.513, p < 0.05 and r = 0.593, p < 0.05, respectively. Hyperactive/inattention correlated negatively with RM lines in the parietal area (r = −707, p < 0.01).Conclusions: These observations may lead to future studies for precise localization of neuropsychiatric symptoms, thereby facilitating directed therapy.

Adhesion dynamics in the neocortex determine the start of migration and the post-migratory orientation of neurons

The neocortex is stereotypically organized into layers of excitatory neurons arranged in a precise parallel orientation. Here we show that dynamic adhesion both preceding and following radial migration is essential for this organization. Neuronal adhesion is regulated by the Mowat-Wilson syndrome-associated transcription factor Zeb2 (Sip1/Zfhx1b) through direct repression of independent adhesion pathways controlled by Neuropilin-1 (Nrp1) and Cadherin-6 (Cdh6). We reveal that to initiate radial migration, neurons must first suppress adhesion to the extracellular matrix. Zeb2 regulates the multipolar stage by transcriptional repression of Nrp1 and thereby downstream inhibition of integrin signaling. Upon completion of migration, neurons undergo an orientation process that is independent of migration. The parallel organization of neurons within the neocortex is controlled by Cdh6 through atypical regulation of integrin signaling via its RGD motif. Our data shed light on the mechanisms that regulate initiation of radial migration and the postmigratory orientation of neurons during neocortical development.

Loss of BAF Complex in Developing Cortex Perturbs Radial Neuronal Migration in a WNT Signaling-Dependent Manner

Radial neuronal migration is a key neurodevelopmental event indispensable for proper cortical laminar organization. Cortical neurons mainly use glial fiber guides, cell adhesion dynamics, and cytoskeletal remodeling, among other discrete processes, to radially trek from their birthplace to final layer positions. Dysregulated radial migration can engender cortical mis-lamination, leading to neurodevelopmental disorders. Epigenetic factors, including chromatin remodelers have emerged as formidable regulators of corticogenesis. Notably, the chromatin remodeler BAF complex has been shown to regulate several aspects of cortical histogenesis. Nonetheless, our understanding of how BAF complex regulates neuronal migration is limited. Here, we report that BAF complex is required for neuron migration during cortical development. Ablation of BAF complex in the developing mouse cortex caused alteration in the cortical gene expression program, leading to loss of radial migration-related factors critical for proper cortical layer formation. Of note, BAF complex inactivation in cortex caused defective neuronal polarization resulting in diminished multipolar-to-bipolar transition and eventual disruption of radial migration of cortical neurons. The abnormal radial migration and cortical mis-lamination can be partly rescued by downregulating WNT signaling hyperactivity in the BAF complex mutant cortex. By implication, the BAF complex modulates WNT signaling to establish the gene expression program required for glial fiber-dependent neuronal migration, and cortical lamination. Overall, BAF complex has been identified to be crucial for cortical morphogenesis through instructing multiple aspects of radial neuronal migration in a WNT signaling-dependent manner.

Periodic Unsteady Kinematics of Hub Flows in a Shrouded Multistage Compressor

Periodic unsteady flow kinematics in a shrouded multistage low-speed axial compressor has been measured for the first time. Data have been acquired at the inlet and exit of a shrouded 3rd-stage stator with a particular focus on the hub flows. The newly found features of the hub flow in a shrouded multistage compressor are different from those at the midspan or in unshrouded (i.e., cantilevered) compressors. First, the merging of the 2nd-stage stator and 3rd-stage rotor wakes causes positive radial migration near the rotor wake pressure surface at the hub of the 3rd-stage stator inlet. Second, the low-momentum labyrinth seal leakage flow of the 3rd-stage stator merges with the 3rd-stage rotor wake to create streamwise vorticity at the 3rd-stage stator inlet hub. Third, contrary to unshrouded stators, suction side hub corner separation in the shrouded 3rd-stage stator reduces rotor wake stretching. Thus, velocity disturbances are attenuated less, and amplitudes of periodic fluctuations in flow angles are larger at the 3rd-stage stator exit hub than at midspan. The positive radial migration of the rotor wake hub flow and wake stretching reduction are expected to decrease efficiency, whereas streamwise vorticity generation is expected to increase efficiency.

ATF5 deficiency causes abnormal cortical development

Activating transcription factor 5 (ATF5) is a member of the cAMP response element binding protein (CREB)/ATF family of basic leucine zipper transcription factors. We previously reported that ATF5-deficient (ATF5−/−) mice exhibited behavioural abnormalities, including abnormal social interactions, reduced behavioural flexibility, increased anxiety-like behaviours, and hyperactivity in novel environments. ATF5−/− mice may therefore be a useful animal model for psychiatric disorders. ATF5 is highly expressed in the ventricular zone and subventricular zone during cortical development, but its physiological role in higher-order brain structures remains unknown. To investigate the cause of abnormal behaviours exhibited by ATF5−/− mice, we analysed the embryonic cerebral cortex of ATF5−/− mice. The ATF5−/− embryonic cerebral cortex was slightly thinner and had reduced numbers of radial glial cells and neural progenitor cells, compared to a wild-type cerebral cortex. ATF5 deficiency also affected the basal processes of radial glial cells, which serve as a scaffold for radial migration during cortical development. Further, the radial migration of cortical upper layer neurons was impaired in ATF5−/− mice. These results suggest that ATF5 deficiency affects cortical development and radial migration, which may partly contribute to the observed abnormal behaviours.