Molecular mechanisms of cadherin function during cortical migration

During development of the cerebral cortex, different types of neurons migrate from distinct origins to create the different cortical layers and settle within them. Along their way, migrating neurons use cell adhesion molecules on their surface to interact with other cells that will play critical roles to ensure that migration is successful. Radially migrating projection neurons interact primarily with radial glia and Cajal-Retzius cells, whereas interneurons originating in the subpallium follow a longer, tangential route and encounter additional cellular substrates before reaching the cortex. Cell-cell adhesion is therefore essential for the correct migration of cortical neurons. Several members of the cadherin superfamily of cell adhesion proteins, which mediate cellular interactions through calcium-dependent, mostly homophilic binding, have been shown to play important roles during neuronal migration of both projection neurons and interneurons. Although several classical cadherins and protocadherins are involved in this process, the most prominent is CDH2. This mini review will explore the cellular and molecular mechanisms underpinning cadherin function during cortical migration, including recent advances in our understanding of the control of adhesive strength through regulation of cadherin surface levels. Keywords: cerebral cortex, neuron, migration, cell surface, adhesion molecules, CDH2, molecular mechanis

Transcriptional control of embryonic and adult neural progenitor activity

Neural precursors generate neurons in the embryonic brain and in restricted niches of the adult brain in a process called neurogenesis. The precise control of cell proliferation and differentiation in time and space required for neurogenesis depends on sophisticated orchestration of gene transcription in neural precursor cells. Much progress has been made in understanding the transcriptional regulation of neurogenesis, which relies on dose- and context-dependent expression of specific transcription factors that regulate the maintenance and proliferation of neural progenitors, followed by their differentiation into lineage-specified cells. Here, we review some of the most widely studied neurogenic transcription factors in the embryonic cortex and neurogenic niches in the adult brain. We compare functions of these transcription factors in embryonic and adult neurogenesis, highlighting biochemical, developmental, and cell biological properties. Our goal is to present an overview of transcriptional regulation underlying neurogenesis in the developing cerebral cortex and in the adult brain

Transcriptional control of embryonic and adult neural progenitor activity

Neural precursors generate neurons in the embryonic brain and in restricted niches of the adult brain in a process called neurogenesis. The precise control of cell proliferation and differentiation in time and space required for neurogenesis depends on sophisticated orchestration of gene transcription in neural precursor cells. Much progress has been made in understanding the transcriptional regulation of neurogenesis, which relies on dose- and context-dependent expression of specific transcription factors that regulate the maintenance and proliferation of neural progenitors, followed by their differentiation into lineage-specified cells. Here, we review some of the most widely studied neurogenic transcription factors in the embryonic cortex and neurogenic niches in the adult brain. We compare functions of these transcription factors in embryonic and adult neurogenesis, highlighting biochemical, developmental, and cell biological properties. Our goal is to present an overview of transcriptional regulation underlying neurogenesis in the developing cerebral cortex and in the adult brain

The neuronal migration hypothesis of dyslexia : a critical evaluation 30 years on

This work was supported by the Wellcome Trust (092071/Z/10/Z to A.P.M., Z.M. and A.V.-B., and 082498/Z/07/Z to D.V.M.B.); L.G.G. receive a Doctoral Training Award from the Medical Research Council; S.P. is a Royal Society University Research Fellow.The capacity for language is one of the key features underlying the complexity of human cognition and its evolution. However, little is known about the neurobiological mechanisms that mediate normal or impaired linguistic ability. For developmental dyslexia, early postmortem studies conducted in the 1980s linked the disorder to subtle defects in the migration of neurons in the developing neocortex. These early studies were reinforced by human genetic analyses that identified dyslexia susceptibility genes and subsequent evidence of their involvement in neuronal migration. In this review, we examine recent experimental evidence that does not support the link between dyslexia and neuronal migration. We critically evaluate gene function studies conducted in rodent models and draw attention to the lack of robust evidence from histopathological and imaging studies in humans. Our review suggests that the neuronal migration hypothesis of dyslexia should be reconsidered, and the neurobiological basis of dyslexia should be approached with a fresh start.PreprintPublisher PDFPeer reviewe

Neuregulin-4 is required for maintaining soma size of pyramidal neurons in the motor cortex

The regulation of neuronal soma size is essential for appropriate brain circuit function and its dysregulation is associated with several neurodevelopmental disorders. A defect in the dendritic growth and elaboration of motor neocortical pyramidal neurons in neonates lacking neuregulin-4 (NRG4) has previously been reported. In this study, we investigated if the loss of NRG4 causes further morphological defects that are specific to these neurons. We analysed the soma size of pyramidal neurons of layers 2/3 and 5 of the motor cortex and a subpopulation of multipolar interneurons in this neocortical region in Nrg4+/+ and Nrg4-/- mice. There were significant decreases in pyramidal neuron soma size in Nrg4-/- mice compared with Nrg4+/+ littermates at all stages studied (P10, P30 and P60). The reduction was especially marked at P10 and in layer 5 pyramidal neurons. Soma size was not significantly different for multipolar interneurons at any age. This in vivo phenotype was replicated in pyramidal neurons cultured from Nrg4-/- mice and was rescued by neuregulin-4 treatment. Analysis of a public single-cell RNA sequencing repository revealed discrete Nrg4 and Erbb4 expression in subpopulations of layer 5 pyramidal neurons, suggesting that the observed defects were due in part to loss of autocrine Nrg4/ErbB4 signalling. The pyramidal phenotype in the motor cortex of Nrg4-/- mice was associated with a lack of Rotarod test improvement in P60 mice, suggesting that absence of NRG4 causes alterations in motor performance

Dbx1-derived pyramidal neurons are generated locally in the developing murine neocortex

The neocortex generates at the dorsal region of the pallium in the forebrain. Several adjacent structures also contribute with neurons to neocortex. Ventral pallium is considered to generate several populations of neurons that arrive through tangential migration to the neocortex. Amongst them are the Cajal-Retzius cells and some transient pyramidal neurons. However, the specific site and timing of generation, trajectory of migration and actual contribution to the pyramidal population remains elusive. Here we investigate the spatio-temporal origin of neuronal populations from ventral pallium in an in vivo model, using a transposase mediated in utero electroporation method in embryonic mouse in vivo. From E11 to E14 cells born at the lateral corner of the neocortical neuroepithelium including the ventral pallium migrated ventro-laterally to settle all areas of the ventral telencephalon. Specifically, neurons migrated into amygdala, olfactory cortices and claustrum. However, we found no evidence for any neurons migrating tangentially towards the neocortex, regardless the antero-posterior level and developmental time of the electroporation. Our results challenge the described ventral-pallial origin of the transient pyramidal neuron population. In order to find the exact origin of cortical neurons that were previously Dbx1-fate mapped we used the promoter region of the murine Dbx1 locus to selectively target Dbx1-expressing progenitors and label their lineage. We found these progenitors in low numbers in all pallial areas, and not only in the ventral pallial ventricular zone. Our findings on the local cortical origin of the Dbx1-expressing pyramidal neurons reconcile the observation of Dbx1 expressing neurons in the cortex without evidence of dorsal tangential migration from ventral pallium and provide a new framework for the origin of the transient Dbx1-derived pyramidal neuron population. We conclude that these neurons are born locally within the dorsal pallial neuroepithelium

Normal radial migration and lamination are maintained in dyslexia-susceptibility candidate gene homolog Kiaa0319 knockout mice

AbstractDevelopmental dyslexia is a common disorder with a strong genetic component, but the underlying molecular mechanisms are still unknown. Several candidate dyslexia-susceptibility genes, including KIAA0319, DYX1C1, and DCDC2, have been identified in humans. RNA interference experiments targeting these genes in rat embryos have shown impairments in neuronal migration, suggesting that defects in radial cortical migration could be involved in the disease mechanism of dyslexia. Here we present the first characterisation of a Kiaa0319 knockout mouse line. Animals lacking KIAA0319 protein do not show anatomical abnormalities in any of the layered structures of the brain. Neurogenesis and radial migration of cortical projection neurons are not altered, and the intrinsic electrophysiological properties of Kiaa0319-deficient neurons do not differ from those of wild-type neurons. Kiaa0319 overexpression in cortex delays radial migration, but does not affect final neuronal position. However, knockout animals show subtle differences suggesting possible alterations in anxiety-related behaviour and in sensorimotor gating. Our results do not reveal a migration disorder in the mouse model, adding to the body of evidence available for Dcdc2 and Dyx1c1 that, unlike in the rat in utero knockdown models, the dyslexia-susceptibility candidate mouse homolog genes do not play an evident role in neuronal migration. However, KIAA0319 protein expression seems to be restricted to the brain, not only in early developmental stages but also in adult mice, indicative of a role of this protein in brain function. The constitutive and conditional knockout lines reported here will be useful tools for further functional analyses of Kiaa0319

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Impacts of the Tropical Pacific/Indian Oceans on the Seasonal Cycle of the West African Monsoon

The current consensus is that drought has developed in the Sahel during the second half of the twentieth century as a result of remote effects of oceanic anomalies amplified by local land–atmosphere interactions. This paper focuses on the impacts of oceanic anomalies upon West African climate and specifically aims to identify those from SST anomalies in the Pacific/Indian Oceans during spring and summer seasons, when they were significant. Idealized sensitivity experiments are performed with four atmospheric general circulation models (AGCMs). The prescribed SST patterns used in the AGCMs are based on the leading mode of covariability between SST anomalies over the Pacific/Indian Oceans and summer rainfall over West Africa. The results show that such oceanic anomalies in the Pacific/Indian Ocean lead to a northward shift of an anomalous dry belt from the Gulf of Guinea to the Sahel as the season advances. In the Sahel, the magnitude of rainfall anomalies is comparable to that obtained by other authors using SST anomalies confined to the proximity of the Atlantic Ocean. The mechanism connecting the Pacific/Indian SST anomalies with West African rainfall has a strong seasonal cycle. In spring (May and June), anomalous subsidence develops over both the Maritime Continent and the equatorial Atlantic in response to the enhanced equatorial heating. Precipitation increases over continental West Africa in association with stronger zonal convergence of moisture. In addition, precipitation decreases over the Gulf of Guinea. During the monsoon peak (July and August), the SST anomalies move westward over the equatorial Pacific and the two regions where subsidence occurred earlier in the seasons merge over West Africa. The monsoon weakens and rainfall decreases over the Sahel, especially in August.Peer reviewe