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Orofaciodigital syndrome I (OFD1–MIM #311200) is a rare ciliopathy characterized by facial dysmorphism, oral cavity, digit, and brain malformations, and cognitive deficits. OFD1 syndrome is an X-linked dominant disorder reported mostly in females. The gene responsible for this condition, OFD1 centriole and centriolar satellite protein (OFD1), is involved in primary cilia formation and several cilia-independent biological processes. The functional and structural integrity of the cilia impacts critical brain development processes, explaining the broad range of neurodevelopmental anomalies in ciliopathy patients. As several psychiatric conditions, such as autism spectrum disorders (ASD) and schizophrenia, are neurodevelopmental in nature, their connections with cilia roles are worth exploring. Moreover, several cilia genes have been associated with behavioral disorders, such as autism. We report on a three-year-old girl with a complex phenotype that includes oral malformations, severe speech delay, dysmorphic features, developmental delay, autism, and bilateral periventricular nodular heterotopia, presenting a de novo pathogenic variant in the OFD1 gene. Furthermore, to the best of our knowledge, this is the first report of autistic behavior in a female patient with OFD1 syndrome. We propose that autistic behavior should be considered a potential feature of this syndrome and that active screening for early signs of autism might prove beneficial for OFD1 syndrome patients.

The ubiquitin-specific protease USP9X has been found to play a role in multiple aspects of neural development including processes of neuronal migrations. In males, hemizygous partial loss of function variants in USP9X lead to a clinical phenotype primarily characterized by intellectual disability, hypotonia, speech and language impairment, behavioral disturbances accompanied by additional clinical features with variable expressivity. Structural brain abnormalities are reported in all cases where neuro-imaging was performed. The most common radiological features described include hypoplasia/agenesis of the corpus callosum, widened ventricles, white matter disturbances, and cerebellar hypoplasia. Here we report a child harboring a missense variant in USP9X presenting with the classical neurodevelopmental phenotype and a previously unreported radiological picture of periventricular heterotopia. This case expands the phenotypic landscape of this emergent condition and supports the critical role of USP9X in neuronal migration processes.

Schizophrenia is thought to be a neurodevelopmental disorder with neuronal migration, differentiation and maturation disturbances. Tau is a microtubule-associated protein with a crucial role in these processes. Lower circulating tau levels have been reported in adults with schizophrenia, but this association has not been investigated in adolescent psychosis. We aimed to test the hypotheses that a) adolescents with early-onset psychosis (EOP; age of onset

Neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASD) and intellectual disability (ID), are a large group of neuropsychiatric illnesses that occur during early brain development, resulting in a broad spectrum of syndromes affecting cognition, sociability, and sensory and motor functions. Despite progress in the discovery of various genetic risk factors thanks to the development of novel genomics technologies, the precise pathological mechanisms underlying the onset of NDDs remain elusive owing to the profound genetic and phenotypic heterogeneity of these conditions. Autism susceptibility candidate 2 (AUTS2) has emerged as a crucial gene associated with a wide range of neuropsychological disorders, such as ASD, ID, schizophrenia, and epilepsy. AUTS2 has been shown to be involved in multiple neurodevelopmental processes; in cell nuclei, it acts as a key transcriptional regulator in neurodevelopment, whereas in the cytoplasm, it participates in cerebral corticogenesis, including neuronal migration and neuritogenesis, through the control of cytoskeletal rearrangements. Postnatally, AUTS2 regulates the number of excitatory synapses to maintain the balance between excitation and inhibition in neural circuits. In this review, we summarize the knowledge regarding AUTS2, including its molecular and cellular functions in neurodevelopment, its genetics, and its role in behaviors.

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)–GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10–2, threshold = 2.5 × 10–2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10–2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10–4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations., Translational Psychiatry, 12 (1), ISSN:2158-3188

Autosomal recessive primary microcephaly (MCPH) is a uncommon disorder due to congenital deficiency in the development of the cerebral cortex, characterized by a head circumference below 2 SD. MCPH is a group of diseases with genetic heterogeneity and has been reported by the Online Mendelian Inheritance In Man® (OMIM) database and associated with 25 different genes. It is known that MCPH cases are most frequently associated with abnormal spindle-like, microcephaly-associated (ASPM) gene mutations. The ASPM protein consists of an N-terminal 81 IQ (isoleucine-glutamine) domain, a calponin-homology domain, and a C-terminal domain. It interacts with calmodulin and calmodulin-related proteins via the IQ domain and acts as a part in mitotic spindle function. The basic characteristics of cases with ASPM gene mutations are microcephaly (below −3 SD) present before 1 year of age, intellectual disability, and the absence of other congenital anomalies. Macroscopic organization of the brain is preserved in cases with ASPM mutation, and a decrease in brain volume, particularly gray matter volume loss and a simplified gyral pattern are observed. Cortical migration defects are a very rare finding in patients with ASPM mutations. In the present study, we aimed to discuss the clinical and genetic findings in 2 cases with cortical dysplasia in which truncated variants in the ASPM gene were detected, particularly in terms of genotype-phenotype correlation in comparison with the literature.

Lissencephaly is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of gyri. The natural course includes developmental delay, mental retardation, epileptic seizures, and microcephaly. Early diagnosis of lissencephaly is very important to give couples reproductive choices. Cranial ultrasonography is often used for the initial evaluation of intracranial abnormalities in fetuses and infants, and we believe that it is a safe and cost-efficient alternative to MRI and CT in many cases. This study combines a case of lissencephaly in our hospital and related literature review, to explore the clinical manifestations, epileptic seizures and ultrasonographic features of the disease, in order to improve the understanding of the disease.

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes. Scala et al. identify six de novo variants in RAC3, which encodes a small GTPase, in 10 unrelated subjects with neurodevelopmental phenotypes. In vivo and in vitro analyses in mice reveal that RAC3 variants cause morpho-functional defects in cortical neurons through variant-specific mechanisms, disrupting corticogenesis.

The 14-3-3 family comprises multifunctional proteins that play a role in neurogenesis, neuronal migration, neuronal differentiation, synaptogenesis and dopamine synthesis. 14-3-3 members function as adaptor proteins and impact a wide variety of cellular and physiological processes involved in the pathophysiology of neurological disorders. Schizophrenia is a psychiatric disorder and knowledge about its pathophysiology is still limited. 14-3-3 have been proven to be linked with the dopaminergic, glutamatergic and neurodevelopmental hypotheses of schizophrenia. Further, research using genetic models has demonstrated the role played by 14-3-3 proteins in neurodevelopment and neuronal circuits, however a more integrative and comprehensive approach is needed for a better understanding of their role in schizophrenia. For instance, we still lack an integrated assessment of the processes affected by 14-3-3 proteins in the dopaminergic and glutamatergic systems. In this context, it is also paramount to understand their involvement in the biology of brain cells other than neurons. Here, we present previous and recent research that has led to our current understanding of the roles 14-3-3 proteins play in brain development and schizophrenia, perform an assessment of their functional protein association network and discuss the use of protein-protein interaction modulators to target 14-3-3 as a potential therapeutic strategy.

Intragravidic and perinatal infections, acting through either direct viral effect or immune‐mediated responses, are recognized causes of liability for neurodevelopmental disorders in the progeny. The large amounts of epidemiological data and the wealth of information deriving from animal models of gestational infections have contributed to delineate, in the last years, possible underpinning mechanisms for this phenomenon, including defects in neuronal migration, impaired spine and synaptic development, and altered activation of microglia. Recently, dysfunctions of the neurovascular unit and anomalies of the brain vasculature have unexpectedly emerged as potential causes at the origin of behavioral abnormalities and psychiatric disorders consequent to prenatal and perinatal infections. This review aims to discuss the up‐to‐date literature evidence pointing to the neurovascular unit and brain vasculature damages as the etiological mechanisms in neurodevelopmental syndromes. We focus on the inflammatory events consequent to intragravidic viral infections as well as on the direct viral effects as the potential primary triggers. These authors hope that a timely review of the literature will help to envision promising research directions, also relevant for the present and future COVID‐19 longitudinal studies., Intragravidic and perinatal infections are recognized causes of liability for neurodevelopmental disorders in the progeny. This review aims to discuss the up‐to‐date evidence pointing to the neurovascular unit and brain vasculature damages as the etiological mechanisms. We focus on the inflammatory events consequent to intragravidic viral infections as well as on the direct viral effects as the potential primary triggers.

Background Proper cerebral cortical development depends on the tightly orchestrated migration of newly born neurons from the inner ventricular and subventricular zones to the outer cortical plate. Any disturbance in this process during prenatal stages may lead to neuronal migration disorders (NMDs), which can vary in extent from focal to global. Furthermore, NMDs show a substantial comorbidity with other neurodevelopmental disorders, notably autism spectrum disorders (ASDs). Our previous work demonstrated focal neuronal migration defects in mice carrying loss-of-function alleles of the recognized autism risk gene WDFY3. However, the cellular origins of these defects in Wdfy3 mutant mice remain elusive and uncovering it will provide critical insight into WDFY3-dependent disease pathology. Methods Here, in an effort to untangle the origins of NMDs in Wdfy3lacZ mice, we employed mosaic analysis with double markers (MADM). MADM technology enabled us to genetically distinctly track and phenotypically analyze mutant and wild-type cells concomitantly in vivo using immunofluorescent techniques. Results We revealed a cell autonomous requirement of WDFY3 for accurate laminar positioning of cortical projection neurons and elimination of mispositioned cells during early postnatal life. In addition, we identified significant deviations in dendritic arborization, as well as synaptic density and morphology between wild type, heterozygous, and homozygous Wdfy3 mutant neurons in Wdfy3-MADM reporter mice at postnatal stages. Limitations While Wdfy3 mutant mice have provided valuable insight into prenatal aspects of ASD pathology that remain inaccessible to investigation in humans, like most animal models, they do not a perfectly replicate all aspects of human ASD biology. The lack of human data makes it indeterminate whether morphological deviations described here apply to ASD patients or some of the other neurodevelopmental conditions associated with WDFY3 mutation. Conclusions Our genetic approach revealed several cell autonomous requirements of WDFY3 in neuronal development that could underlie the pathogenic mechanisms of WDFY3-related neurodevelopmental conditions. The results are also consistent with findings in other ASD animal models and patients and suggest an important role for WDFY3 in regulating neuronal function and interconnectivity in postnatal life.

Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. DCX is a microtubule-associated protein which plays a key role during neurodevelopment in neuronal migration and differentiation. Dcx knockout (KO) mice show disorganized hippocampal pyramidal neurons. The CA2/CA3 pyramidal cell layer is present as two abnormal layers and disorganized CA3 KO pyramidal neurons are also more excitable than wild-type (WT) cells. To further identify abnormalities, we characterized Dcx KO hippocampal neurons at subcellular, molecular and ultrastructural levels. Severe defects were observed in mitochondria, affecting number and distribution. Also, the Golgi apparatus was visibly abnormal, increased in volume and abnormally organized. Transcriptome analyses from laser microdissected hippocampal tissue at postnatal day 60 (P60) highlighted organelle abnormalities. Ultrastructural studies of CA3 cells performed in P60 (young adult) and > 9 months (mature) tissue showed that organelle defects are persistent throughout life. Locomotor activity and fear memory of young and mature adults were also abnormal: Dcx KO mice consistently performed less well than WT littermates, with defects becoming more severe with age. Thus, we show that disruption of a neurodevelopmentally-regulated gene can lead to permanent organelle anomalies contributing to abnormal adult behavior. ispartof: NEUROBIOLOGY OF DISEASE vol:168 ispartof: location:United States status: published

During the past few decades, we have witnessed an impressive gain in the knowledge regarding the basic mechanisms underlying human neuronal migration disorders by the usage of mouse models. Nevertheless, despite the remarkable conservation both in the genetic encoded information and the developmental processes, there are still numerous important differences between human and mouse. This may explain the vast excitement following the realization that technological breakthroughs enabled generating tissue-like human-based organoids for modeling human neuronal migration diseases. This review will provide a short introduction on human and mouse neuronal migration processes, and highlight human brain organoid models of neuronal migration diseases.

The development and evolution of mammalian higher cognition are represented by gyrification of the laminar cerebral cortex and astrocyte development, but their mechanisms and interrelationships remain unknown. Here, we show that localized astrogenesis plays an important role in gyri formation in the gyrencephalic cerebral cor-tex. In functional genetic experiments, we show that reducing astrocyte number prevents gyri formation in the ferret cortex, while increasing astrocyte number in mice, which do not have cortical folds, can induce gyrus-like protrusions. Morphometric analyses demonstrate that the vertical expansion of deep pallial regions achieved by localized astrogenesis is crucial for gyri formation. Furthermore, our findings suggest that localized astrogenesis by a positive feedback loop of FGF signaling is an important mechanism underlying cortical folding in gyren-cephalic mammalian brains. Our findings reveal both the cellular mechanisms and the mechanical principle of gyrification in the mammalian brain. This work was supported by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT); Takeda Science Foundation; the Uehara Memorial Foundation; the Naito Foundation; European Research Council (ERC) Starting Grant 281961 AstroFunc; European Commission Horizon 2020 Action NCBio 951923; European Commission FP7-PEOPLE-2012-IEF 331018 PlasticAstros; Kanazawa University SAKIGAKE Project 2018; and Kanazawa University CHOZEN Project.

Resumen: Introducción: La infección por citomegalovirus es la infección congénita más frecuente en los países desarrollados y una de las principales causas de retraso psicomotor y sordera neurosensorial de origen infeccioso.El presente estudio tiene como objetivos describir las características clínico-analíticas y de neuroimagen de los pacientes con secuelas neurológicas secundarias a la infección congénita por citomegalovirus y compararlas con el grupo de pacientes con infección congénita por citomegalovirus que no presentaron clínica neurológica durante su seguimiento. Material y Métodos: Estudio de cohortes retrospectivo, observacional. Se incluyeron todos los casos de infección congénita por citomegalovirus desde 2003 hasta 2018 y se evaluaron las secuelas neurológicas a corto-medio plazo. Se compararon datos prenatales, perinatales y posnatales de los pacientes con secuelas neurológicas frente a los que no las presentaron. Resultados: En el periodo descrito se registraron 60 pacientes con infección congénita por citomegalovirus: un 65% presentó afectación neurológica durante su periodo de seguimiento (retraso psicomotor 62,2%; microcefalia 61,5%, hipoacusia 46,2%; trastornos motores 27,8%; epilepsia 20,5% y coriorretinitis 5,6%). En el grupo de pacientes que presentó secuelas, la presencia de clínica en el periodo neonatal así como las alteraciones en el estudio de neuroimagen fueron más frecuentes y ambas fueron estadísticamente significativas respecto al grupo asintomático. Los pacientes con afectación neurológica también presentaron mayor puntuación en la escala de neuroimagen según Noyola et al. Conclusiones: La sintomatología al nacimiento y ciertos hallazgos en la neuroimagen, como la presencia de alteraciones de la sustancia blanca o trastornos de la migración neuronal, podrían predecir las secuelas neurocognitivas en los pacientes con infección congénita por citomegalovirus. Abstract: Introduction: The infection due to cytomegalovirus is the most common congenital infection in developed countries, and on of the main causes of psychomotor impairment and neurosensory hearing loss of infectious origin.The present study has its objectives to describe the clinical-analytical and neuroimaging of patients with secondary neurological sequelae secondary to the congenital cytomegalovirus infection and then compare them with the group of patients with a congenital cytomegalovirus infection that did not have neurological symptoms during their follow-up. Material and methods: A retrospective, observational, cohort study was conducted that included all the cases of congenital cytomegalovirus infection from 2003 until 2018 and the short-medium term neurological sequelae were evaluated. Prenatal, perinatal, and postnatal data of patients with neurological sequelae were compared against those that did not present with any. Results: A total of 60 patients with congenital cytomegalovirus infection were recorded during the study period, with 65% having neurological involvement during their follow-up period (62.2% with psychomotor impairment, 61.5% with microcephaly, 46.2% loss of hearing, 27.8% motor disorders, 20.5% epilepsy, and 5.6% with chorioretinitis). In the patient group that had sequelae, the presence of clinical symptoms during the neonatal period, as well as changes in the neuroimaging study, were the most common, with both being statistically significant compared to the asymptomatic group. The patients with neurological involvement also had a higher score on the Noyola et al. neuroimaging scale. Conclusions: The symptoms at birth, and certain findings in the neuroimaging, like the changes in the white matter or neuronal migration disorders, could predict neurocognitive sequelae in patients with congenital cytomegalovirus infection.

sProper dendrite morphogenesis and neuronal migration are crucial for cerebral cortex development and neural circuit formation. In this study, we sought to determine if the histone deacetylase HDAC6 plays a role in dendrite development and neuronal migration of pyramidal neurons during cerebral cortex development. It was observed that knockdown of HDAC6 leads to defective dendrite morphogenesis and abnormal Golgi polarization in vitro, and the expression of wild type cortactin or deacetyl-mimetic cortactin 9KR rescued the defective phenotypes of the HDAC6 knockdown neurons. This suggests that HDAC6 promotes dendritic growth and Golgi polarization through cortactin deacetylation in vitro. We also demonstrated that ectopic expression of SIRT2, a cytoplasmic NAD+ − dependent deacetylase, suppresses the defects of HDAC6 knockdown neurons. These results indicate that HDAC6 and SIRT2 may be functionally redundant during dendrite development. Neurons transfected with both HDAC6 and SIRT2 shRNA or acetyl-mimetic cortactin 9KQ showed slow radial migration compared to the control cells during cerebral cortex development. Furthermore, a large portion of cortactin 9KQ-expressing pyramidal neurons at layer II/III in the cerebral cortex failed to form an apical dendrite toward the pial surface and had an increased number of primary dendrites, and the percentage of neurons with dendritic Golgi decreased in cortactin 9KQ-expressing cells, compared to control neurons. Taken together, this study suggests that HDAC6 and SIRT2 regulate neuronal migration and dendrite development through cortactin deacetylation in vivo.

Environmental chemical and physical cues dynamically interact with migrating neurons and sprouting axons, and in particular, the gradients of environmental cues are regarded as one of the factors intimately involved in the neuronal movement. Since a growth cone was first described by Cajal, more than one century ago, chemical gradients have been suggested as one of the mechanisms by which the neurons determine proper paths and destinations. However, the gradients of physical cues, such as stiffness and topography, which also interact constantly with the neurons and their axons as a component of the extracellular environments, have rarely been noted regarding the guidance of neurons, despite their gradually increasingly reported influences in the case of nonneuronal-cell migration. In this review, we discuss chemical (i.e., chemo- and hapto-) and physical (i.e., duro-) taxis phenomena on the movement of neurons including axonal elongation. In addition, we suggest topotaxis, the most recently proposed physical-taxis phenomenon, as another potential mechanism in the neuronal movement, based on the reports of neuronal recognition of and responses to nanotopography.

The highly organized laminar structure of the mammalian brain is dependent on successful neuronal migration, and migration deficits can cause lissencephaly and behavioral and cognitive defects. Here, we investigated the contribution of neuronal migration dysregulation to anesthesia-induced neurotoxicity in the fetal brain. Pregnant C57BL/6 mice at embryonic day 14.5 received 2.5% sevoflurane daily for two days. Cortical neuron migration and axon lengths were evaluated using GFP immunostaining. Morris water maze tests were performed to assess the effects of sevoflurane exposure on spatial memory in offspring. We found that sevoflurane exposure decreased axon length and caused cognitive defects in young mice. RNA sequencing revealed that these defects were associated with reduced neuro-oncological ventral antigen 2 (Nova2) expression. In utero electroporation experiments using Nova2 shRNA recapitulated this finding. Nova2 shRNA inhibited neuronal migration and decreased axon lengths. Finally, we found that Netrin-1/Deleted in Colorectal Cancer (Dcc) proteins acted downstream of Nova2 to suppresses neuronal migration. These findings describe a novel mechanism by which prenatal anesthesia exposure affects embryonic neural development and postnatal behavior.

Summary The neural stem cells (NSCs) residing in the olfactory epithelium (OE) regenerate damaged olfactory sensory neurons throughout adulthood. The accessibility and availability of these NSCs in living individuals, including humans, makes them a promising candidate for harvesting their potential for cell replacement therapies. However, this requires an in-depth understanding of their developmental potential after grafting. Here, we investigated the developmental potential and plasticity of mouse OE-derived NSCs after grafting into the adult subventricular zone (SVZ) neurogenic niche. Our results showed that OE-derived NSCs integrate and proliferate just like endogenous SVZ stem cells, migrate with similar dynamics as endogenous neuroblasts toward the olfactory bulb, and mature and acquire similar electrophysiological properties as endogenous adult-born bulbar interneurons. These results reveal the developmental potential and plasticity of OE-derived NSCs in vivo and show that they can respond to heterotopic neurogenic cues to adapt their phenotype and become functional neurons in ectopic brain regions., Graphical Abstract, Highlights • OE-derived NSCs integrate in the SVZ after heterotopic transplantation • OE-derived NSCs respond to SVZ niche factors and change their developmental program • The development of OE-derived and SVZ NSCs are indistinguishable • OE-derived NSCs grafted into the SVZ become functional bulbar interneurons, In this article, Saghatelyan and colleagues show that olfactory epithelium-derived neural stem cells adapt their developmental program in response to heterotopic neurogenic niche factors after grafting in vivo. They migrate and differentiate into ectopic brain region neurons that are indistinguishable in their morpho-functional properties from endogenous adult-born neurons.

The cerebral cortex is a structure that underlies various brain functions, including cognition and language. Mammalian cerebral cortex starts developing during the embryonic period with the neural progenitor cells generating neurons. Newborn neurons migrate along progenitors’ radial processes from the site of their origin in the germinal zones to the cortical plate, where they mature and integrate in the forming circuitry. Cell biological features of neural progenitors, such as the location and timing of their mitoses, together with their characteristic morphologies, can directly or indirectly regulate the abundance and the identity of their neuronal progeny. Alterations in the complex and delicate process of cerebral cortex development can lead to malformations of cortical development (MCDs). They include various structural abnormalities that affect the size, thickness and/or folding pattern of the developing cortex. Their clinical manifestations can entail a neurodevelopmental disorder, such as epilepsy, developmental delay, intellectual disability, or autism spectrum disorder. The recent advancements of molecular and neuroimaging techniques, along with the development of appropriate in vitro and in vivo model systems, have enabled the assessment of the genetic and environmental causes of MCDs. Here we broadly review the cell biological characteristics of neural progenitor cells and focus on those features whose perturbations have been linked to MCDs.

Changes in the transcription factor (TF) expression are critical for brain development, and they may also underlie neurodevelopmental disorders. Indeed, T-box brain1 (Tbr1) is a TF crucial for the formation of neocortical layer VI, and mutations and microdeletions in that gene are associated with malformations in the human cerebral cortex, alterations that accompany autism spectrum disorder (ASD). Interestingly, Tbr1 upregulation has also been related to the occurrence of ASD-like symptoms, although limited studies have addressed the effect of increased Tbr1 levels during neocortical development. Here, we analysed the impact of Tbr1 misexpression in mouse neural progenitor cells (NPCs) at embryonic day 14.5 (E14.5), when they mainly generate neuronal layers II–IV. By E18.5, cells accumulated in the intermediate zone and in the deep cortical layers, whereas they became less abundant in the upper cortical layers. In accordance with this, the proportion of Sox5+ cells in layers V–VI increased, while that of Cux1+ cells in layers II–IV decreased. On postnatal day 7, fewer defects in migration were evident, although a higher proportion of Sox5+ cells were seen in the upper and deep layers. The abnormal neuronal migration could be partially due to the altered multipolar-bipolar neuron morphologies induced by Tbr1 misexpression, which also reduced dendrite growth and branching, and disrupted the corpus callosum. Our results indicate that Tbr1 misexpression in cortical NPCs delays or disrupts neuronal migration, neuronal specification, dendrite development and the formation of the callosal tract. Hence, genetic changes that provoke ectopic Tbr1 upregulation during development could provoke cortical brain malformations.

The amygdala is a hyperspecialized brain region composed of strongly inter- and intraconnected nuclei involved in emotional learning and behavior. The cellular heterogeneity of the amygdalar nuclei has complicated straightforward conclusions on their developmental origin, and even resulted in contradictory data. Recently, the concentric ring theory of the pallium and the radial histogenetic model of the pallial amygdala have cleared up several uncertainties that plagued previous models of amygdalar development. Here, we provide an extensive overview on the developmental origin of the nuclei of the amygdaloid complex. Starting from older gene expression data, transplantation and lineage tracing studies, we systematically summarize and reinterpret previous findings in light of the novel perspectives on amygdalar development. In addition, migratory routes that these cells take on their way to the amygdala are explored, and known transcription factors and guidance cues that seemingly drive these cells toward the amygdala are emphasized. We propose some future directions for research on amygdalar development and highlight that a better understanding of its development could prove critical for the treatment of several neurodevelopmental and neuropsychiatric disorders. ispartof: Frontiers In Neuroanatomy vol:15 ispartof: location:Switzerland status: Published online

The 17p13.3 chromosome region is often deleted or duplicated in humans, resulting in severe neurodevelopmental disorders such as Miller–Dieker syndrome (MDS) and 17p13.3 duplication syndrome. Lissencephaly can also be caused by gene mutations or deletions of a small piece of the 17p13.3 region, including a single gene or a few genes. PAFAH1B1 gene, coding for LIS1 protein, is a responsible gene for lissencephaly and MDS and regulates neuronal migration by controlling microtubules (MTs) and cargo transport along MTs via dynein. CRK is a downstream regulator of the reelin signaling pathways and regulates neuronal migration. YWHAE, coding for 14-3-3ε, is also responsible for MDS and regulates neuronal migration by binding to LIS1-interacting protein, NDEL1. Although these three proteins are known to be responsible for neuronal migration defects in MDS, there are 23 other genes in the MDS critical region on chromosome 17p13.3, and little is known about their functions in neurodevelopment, especially in neuronal migration. This review will summarize the recent progress on the functions of LIS1, CRK, and 14-3-3ε and describe the recent findings of other molecules in the MDS critical regions in neuronal migration.

Electrical activity plays crucial roles in neural circuit formation and remodeling. During neocortical development, neurons are generated in the ventricular zone, migrate to their correct position, elongate dendrites and axons, and form synapses. In this review, we summarize the functions of ion channels and transporters in neocortical development. Next, we discuss links between neurological disorders caused by dysfunction of ion channels (channelopathies) and neocortical development. Finally, we introduce emerging optical techniques with potential applications in physiological studies of neocortical development and the pathophysiology of channelopathies.

Radial neuron migration in the developing cerebral cortex is a complex journey, starting in the germinal zones and ending in the cortical plate. In mice, migratory distances can reach several hundreds of microns, or millimeters in humans. Along the migratory path, radially migrating neurons slither through cellularly dense and complex territories before they reach their final destination in the cortical plate. This task is facilitated by radial glia, the neural stem cells of the developing cortex. Indeed, radial glia have a unique bipolar morphology, enabling them to serve as guides for neuronal migration. The key guiding structure of radial glia is the basal process, which traverses the entire thickness of the developing cortex. Neurons recognize the basal process as their guide and maintain physical interactions with this structure until the end of migration. Thus, the radial glia basal process plays a key role during radial migration. In this review, we highlight the pathways enabling neuron-basal process interactions during migration, as well as the known mechanisms regulating the morphology of the radial glia basal process. Throughout, we describe how dysregulation of these interactions and of basal process morphology can have profound effects on cortical development, and therefore lead to neurodevelopmental diseases.

To establish functional networks, neurons must migrate to their appropriate destinations and then extend axons toward their target cells. These processes depend on the advances of growth cones that located at the tips of neurites. Axonal growth cones generate driving forces by sensing their local microenvironment and modulating cytoskeletal dynamics and actin-adhesion coupling (clutch coupling). Decades of research have led to the identification of guidance molecules, their receptors, and downstream signaling cascades for regulating neuronal migration and axonal guidance; however, the molecular machineries required for generating forces to drive growth cone advance and navigation are just beginning to be elucidated. At the leading edge of neuronal growth cones, actin filaments undergo retrograde flow, which is powered by actin polymerization and actomyosin contraction. A clutch coupling between F-actin retrograde flow and adhesive substrate generates traction forces for growth cone advance. The present study describes a detailed protocol for monitoring F-actin retrograde flow by single speckle imaging. Importantly, when combined with an F-actin marker Lifeact, this technique can quantify 1) the F-actin polymerization rate and 2) the clutch coupling efficiency between F-actin retrograde flow and the adhesive substrate. Both are critical variables for generating forces for growth cone advance and navigation. In addition, the present study describes a detailed protocol of traction force microscopy, which can quantify 3) traction force generated by growth cones. Thus, by coupling the analyses of single speckle imaging and traction force microscopy, investigators can monitor the molecular mechanics underlying growth cone advance and navigation.

Cephalopods have evolved nervous systems that parallel the complexity of mammalian brains in terms of neuronal numbers and richness in behavioral output. How the cephalopod brain develops has only been described at the morphological level, and it remains unclear where the progenitor cells are located and what molecular factors drive neurogenesis. Using histological techniques, we located dividing cells, neural progenitors and postmitotic neurons in Octopus vulgaris embryos. Our results indicate that an important pool of progenitors, expressing the conserved bHLH transcription factors achaete-scute or neurogenin, is located outside the central brain cords in the lateral lips adjacent to the eyes, suggesting that newly formed neurons migrate into the cords. Lineage-tracing experiments then showed that progenitors, depending on their location in the lateral lips, generate neurons for the different lobes, similar to the squid Doryteuthis pealeii. The finding that octopus newborn neurons migrate over long distances is reminiscent of vertebrate neurogenesis and suggests it might be a fundamental strategy for large brain development., eLife digest Octopuses have evolved incredibly large and complex nervous systems that allow them to perform impressive behaviors, like plan ahead, navigate and solve puzzles. The nervous system of the common octopus (also known as Octopus vulgaris) contains over half a billion nerves cells called neurons, similar to the number found in small primates. Two thirds of these cells reside in the octopuses’ arms, while the rest make-up a central brain that sits between their eyes. Very little is known about how this central brain forms in the embryo, including where the cells originate and which molecular factors drive their maturation in to adult cells. To help answer these questions, Deryckere et al. studied the brain of Octopus vulgaris at different stages of early development using various cell staining and imaging techniques. The experiments identified an important pool of dividing cells which sit in an area outside the central brain called the ‘lateral lips’. In these cells, genes known to play a role in neural development in other animals are active, indicating that the cells had not reached their final, mature state. In contrast, the central brain did not seem to contain any of these immature cells at the point when it was growing the most. To investigate this further, Deryckere et al. used fluorescent markers to track the progeny of the dividing cells during development. This revealed that cells in the lateral lips take on a specific neuronal fate before migrating to their target region in the central brain. Newly matured neurons have also been shown to travel large distances in the embryos of vertebrates, suggesting that this mechanism may be a common strategy for building large, complex brains. Although the nervous system of the common octopus is comparable to mammals, they evolved from a very distant branch of the tree of life; indeed, their last common ancestor was a worm-like animal that lived about 600 million years ago. Studying the brain of the common octopus, as done here, could therefore provide new insights into how complex nervous systems, including our own, evolved over time.

As neurons are often born at positions different than where they ultimately function, neuronal migration is key to ensure successful nervous system development. Radial migration during which neurons featuring unipolar and bipolar morphology, employ pre-existing processes or underlying cells for directional guidance, is the most well explored neuronal migration mode. However, how neurons that display multipolar morphology, without such processes, move through highly crowded tissue environments towards their final positions remains elusive. To understand this, we here investigated multipolar migration of horizontal cells in the zebrafish retina. We found that horizontal cells tailor their movements to the environmental spatial constraints of the crowded retina, by featuring several characteristics of amoeboid migration. These include cell and nucleus shape changes, and persistent rearward polarization of stable F-actin, which enable horizontal cells to successfully move through the crowded retina. Interference with the organization of the developing retina by changing nuclear properties or overall tissue architecture, hampers efficient horizontal cell migration and layer formation. Thus, cell-tissue interplay is crucial for efficient migration of horizontal cells in the retina. In view of high proportion of multipolar neurons, the here uncovered ameboid-like neuronal migration mode might also be crucial in other areas of the developing brain.

Galanin, one of the most inducible neuropeptides, is widely present in developing brains, and its expression is altered by pathologic events (e.g., epilepsy, ischemia, and axotomy). The roles of galanin in brain development under both normal and pathologic conditions have been hypothesized, but the question of how galanin is involved in fetal and early postnatal brain development remains largely unanswered. In this study, using granule cell migration in the cerebellum of early postnatal mice (both sexes) as a model system, we examined the role of galanin in neuronal cell migration during normal development and after brain injury. Here we show that, during normal development, endogenous galanin participates in accelerating granule cell migration via altering the Ca2+ and cAMP signaling pathways. Upon brain injury induced by the application of cold insults, galanin levels decrease at the lesion sites, but increase in the surroundings of lesion sites. Granule cells exhibit the following corresponding changes in migration: (1) slowing down migration at the lesion sites; and (2) accelerating migration in the surroundings of lesion sites. Experimental manipulations of galanin signaling reduce the lesion site-specific changes in granule cell migration, indicating that galanin plays a role in such deficits in neuronal cell migration. The present study suggests that manipulating galanin signaling may be a potential therapeutic target for acutely injured brains during development.SIGNIFICANCE STATEMENT Deficits in neuronal cell migration caused by brain injury result in abnormal development of cortical layers, but the underlying mechanisms remain to be determined. Here, we report that on brain injury, endogenous levels of galanin, a neuropeptide, are altered in a lesion site-specific manner, decreasing at the lesion sites but increasing in the surroundings of lesion sites. The changes in galanin levels positively correlate with the migration rate of immature neurons. Manipulations of galanin signaling ameliorate the effects of injury on neuronal migration and cortical layer development. These results shed a light on galanin as a potential therapeutic target for acutely injured brains during development.

Cell polarity is fundamentally important for understanding brain development. Here, we hypothesize that the inheritance and flexibility of cell polarity during neocortex development could be implicated in neocortical evolutionary expansion. Molecular and morphological features of cell polarity may be inherited from one type of progenitor cell to the other and finally transmitted to neurons. Furthermore, key cell types, such as basal progenitors and neurons, exhibit a highly flexible polarity. We suggest that both inheritance and flexibility of cell polarity are implicated in the amplification of basal progenitors and tangential dispersion of neurons, which are key features of the evolutionary expansion of the neocortex.

Octopuses have evolved incredibly large and complex nervous systems that allow them to perform impressive behaviors, like plan ahead, navigate and solve puzzles. The nervous system of the common octopus (also known as Octopus vulgaris) contains over half a billion nerves cells called neurons, similar to the number found in small primates. Two thirds of these cells reside in the octopuses’ arms, while the rest make-up a central brain that sits between their eyes. Very little is known about how this central brain forms in the embryo, including where the cells originate and which molecular factors drive their maturation in to adult cells. To help answer these questions, Deryckere et al. studied the brain of Octopus vulgaris at different stages of early development using various cell staining and imaging techniques. The experiments identified an important pool of dividing cells which sit in an area outside the central brain called the ‘lateral lips’. In these cells, genes known to play a role in neural development in other animals are active, indicating that the cells had not reached their final, mature state. In contrast, the central brain did not seem to contain any of these immature cells at the point when it was growing the most. To investigate this further, Deryckere et al. used fluorescent markers to track the progeny of the dividing cells during development. This revealed that cells in the lateral lips take on a specific neuronal fate before migrating to their target region in the central brain. Newly matured neurons have also been shown to travel large distances in the embryos of vertebrates, suggesting that this mechanism may be a common strategy for building large, complex brains. Although the nervous system of the common octopus is comparable to mammals, they evolved from a very distant branch of the tree of life; indeed, their last common ancestor was a worm-like animal that lived about 600 million years ago. Studying the brain of the common octopus, as done here, could therefore provide new insights into how complex nervous systems, including our own, evolved over time.

Summary In development, almost all stratified neurons must migrate from their birthplace to the appropriate neural layer. Photoreceptors reside in the most apical layer of the retina, near their place of birth. Whether photoreceptors require migratory events for fine-positioning and/or retention within this layer is not well understood. Here, we show that photoreceptor nuclei of the developing mouse retina cyclically exhibit rapid, dynein-1-dependent translocation toward the apical surface, before moving more slowly in the basal direction, likely due to passive displacement by neighboring retinal nuclei. Attenuating dynein 1 function in rod photoreceptors results in their ectopic basal displacement into the outer plexiform layer and inner nuclear layer. Synapse formation is also compromised in these displaced cells. We propose that repeated, apically directed nuclear translocation events are necessary to ensure retention of post-mitotic photoreceptors within the emerging outer nuclear layer during retinogenesis, which is critical for correct neuronal lamination., Graphical abstract, Highlights • Photoreceptor nuclei exhibit apico-basal motility in the developing mouse retina • Rapid apically directed nuclear translocation is powered by dynein 1 • Dynein 1 disruption impedes rapid apical nuclear translocation, causing displacement • Synapse formation is disrupted in basally displaced photoreceptors, Photoreceptors occupy a defined layer in the retina. Aghaizu et al. show that mammalian rod and cone photoreceptors use repeated, dynein-1-driven apically directed nuclear translocations for fine-positioning and retention within this layer. Dynein 1 disruption in photoreceptors results in ectopic displacement beyond the photoreceptor layer and impaired synapse formation.

Like other sensory systems, the visual system is topographically organized: Its sensory neurons, the photoreceptors, and their targets maintain point-to-point correspondence in physical space, forming a retinotopic map. The iterative wiring of circuits in the visual system conveniently facilitates the study of its development. Over the past few decades, experiments in Drosophila have shed light on the principles that guide the specification and connectivity of visual system neurons. In this review, we describe the main findings unearthed by the study of the Drosophila visual system and compare them with similar events in mammals. We focus on how temporal and spatial patterning generates diverse cell types, how guidance molecules distribute the axons and dendrites of neurons within the correct target regions, how vertebrates and invertebrates generate their retinotopic map, and the molecules and mechanisms required for neuronal migration. We suggest that basic principles used to wire the fly visual system are broadly applicable to other systems and highlight its importance as a model to study nervous system development.

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.

Modeling neurological disorders is challenging because they often have both endogenous and exogenous causes. Brain organoids consist of three-dimensional (3D) self-organizing brain tissue which increasingly is being used to model various aspects of brain development and disorders, such as the generation of neurons, neuronal migration, and functional networks. These organoids have been recognized as important in vitro tools to model developmental features of the brain, including neurological disorders, which can provide insights into the molecular mechanisms involved in those disorders. In this review, we describe recent advances in the generation of two-dimensional (2D), 3D, and blood-brain barrier models that were derived from induced pluripotent stem cells (iPSCs) and we discuss their advantages and limitations in modeling diseases, as well as explore the development of a vascularized and functional 3D model of brain processes. This review also examines the applications of brain organoids for modeling major neurodegenerative diseases and neurodevelopmental disorders.

Congenital infection of the central nervous system by human cytomegalovirus (HCMV) is a leading cause of permanent sequelae, including mental retardation or neurodevelopmental abnormalities. The most severe complications include smooth brain or polymicrogyria, which are both indicative of abnormal migration of neural cells, although the underlying mechanisms remain to be determined. To gain better insight on the pathogenesis of such sequelae, we assessed the expression levels of a set of neurogenesis-related genes, using HCMV-infected human neural stem cells derived from embryonic stem cells (NSCs). Among the 84 genes tested, we found dramatically increased expression of the gene PAFAH1B1, encoding LIS1 (lissencephaly-1), in HCMV-infected versus uninfected NSCs. Consistent with these findings, western blotting and immunofluorescence analyses confirmed the increased levels of LIS1 in HCMV-infected NSCs at the protein level. We next assessed the migratory abilities of HCMV-infected NSCs and observed that infection strongly impaired the migration of NSCs, without detectable effect on their proliferation. Moreover, we observed increased immunostaining for LIS1 in brains of congenitally infected fetuses, but not in control samples, highlighting the clinical relevance of our findings. Of note, PAFAH1B1 mutations (resulting in either haploinsufficiency or gain of function) are primary causes of hereditary neurodevelopmental diseases. Notably, mutations resulting in PAFAH1B1 haploinsufficiency cause classic lissencephaly. Taken together, our findings suggest that PAFAH1B1 is a critical target of HCMV infection. They also shine a new light on the pathophysiological basis of the neurological outcomes of congenital HCMV infection, by suggesting that defective neural cell migration might contribute to the pathogenesis of the neurodevelopmental sequelae of infection. © 2021 The Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.

A 5-month-old patient was first evaluated for a hypotonic hyporeflexic syndrome; over years, the phenotype evolved to involve ataxia, developmental delay, and coarse facies. Brain MRI showed abnormal configuration of cerebellar folia, rearranged in radial shape (figure). Whole exome sequencing analysis revealed the c.512 G>A (p.G171D) de novo mutation in EBF3 . EBF3 gene function is crucial for neuronal migration during corticogenesis.1 Cerebellar foliation is complex: folia sprout from anchoring centers,2 whose distribution and number determine the shape of lobules and fissures; EBF3 mutations may disrupt this process, thus causing the peculiar cerebellar lobule appearance seen here.

Lissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with lissencephaly, accounting for approximately 80% of disease. Here we report on 12individuals with a unique form of lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant lissencephaly, similar to PAFAH1B1-associated lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, "ribbon-like" heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other lissencephaly-encoded cytoskeletal proteins such as α-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly.

Cyclin-dependent kinase 5 (Cdk5) controls neuronal migration in the developing cortex when multipolar newborn neurons transform to become bipolar. However, by which mechanisms Cdk5 controls cell adhesion in migrating neurons are not fully understood. In this study, we examined the functional interaction between Cdk5 and N-cadherin (Ncad) in newborn neurons when they undergo the multipolar to bipolar transition in the intermediate zone (IZ). Detailed expression analysis revealed that both Cdk5 and Ncad were present in GFP-electroporated migrating neurons in the IZ. Misexpression of dominant negative Cdk5 into the embryonic brains stalled neuronal locomotion in the lower IZ in which arrested cells were round or multipolar. When Ncad was co-introduced with Cdk5DN, however, cells continue to migrate into the cortical plate (CP) and migrating neurons acquired typical bipolar morphology with a pia-directed leading process. Similarly, downregulation of CDK5 resulted in lesser aggregation ability, reversed by the expression of Ncad in vitro. Down-regulation of activity or protein level of CDK5 did not alter the total amount of NCAD proteins but lowered its surface expression in cells. Lastly, expression of CDK5 and NCAD overlapped in the IZ of the human fetal cortex, indicating that the role of Cdk5 and Ncad in neuronal migration is evolutionarily conserved.

This study investigated the ability of intra-subventricular zone (SVZ) administration of cerebral dopamine neurotrophic factor (CDNF) on neural progenitor cells (NPCs) attraction from the SVZ toward the 6-hydroxydopamine (6-OHDA)-lesioned striatum and improvement of motor dysfunctions in Parkinsonian rats. Male Wistar rats were assigned to four groups of the sham model (Sham), 6-OHDA-lesioned (OH), 6-OHDA-lesioned plus CDNF vehicle (OH+Vehicle), and 6-OHDA-lesioned plus CDNF (OH+CDNF). The animal model of Parkinson's disease (PD) was induced by unilateral intra-striatal infusion of 6-OHDA. Rats in the treatment groups received an intra-SVZ injection of CDNF or the vehicle of CDNF two weeks after PD model induction and were then subjected to the beam and bar tests on days 7, 14, and 21 after CDNF injection. Bromodeoxyuridine (BrdU) was intraperitoneally injected to label newly generated cells. Migration and proliferation of NPCs were assessed by BrdU/doublecortin (DCX) double immunofluorescence method on days 7, 14, and 21 after CDNF infusion. 6-OHDA in the OH group induced catalepsy and increased elapsed time in the beam test compared to the Sham group. However, administration of CDNF improved the motor performance and increased the number of DCX expressing neuroblasts in the SVZ as compared to the OH and OH+Vehicle groups. CDNF also enhanced cell proliferation and increased the number of migrated BrdU- and DCX-positive cells toward the lesioned striatum in the OH+CDNF group. These results suggest that CDNF enhances the proliferation and migration of neural stem cells (NSCs) toward the lesioned striatum accompanied by improvement of PD-induced motor dysfunctions., EXCLI Journal;Vol. 18 2019

Tetraspanins, such as CD81, can form lateral associations with each other and with other transmembrane proteins. These interactions may underlie CD81 functions in multiple cellular processes, such as adhesion, morphology, migration, and differentiation. Since CD81's role in neuronal cells' migration has not been established, we here evaluated effects of CD81 on the migratory phenotype of SH-SY5Y neuroblastoma cells. CD81 was found enriched at SH-SY5Y cell's membrane, co-localizing with its interactor filamentous-actin (F-actin) in migratory relevant structures of the leading edge (filopodia, stress fibers, and adhesion sites). CD81 overexpression increased the number of cells with a migratory phenotype, in a potentially phosphatidylinositol 3 kinase (PI3K)-Ak strain transforming (AKT) mediated manner. Indeed, CD81 also co-localized with AKT, a CD81-interactor and actin remodeling agent, at the inner leaflet of the plasma membrane. Pharmacologic inhibition of PI3K, the canonical AKT activator, led both to a decrease in the acquisition of a migratory phenotype and to a redistribution of intracellular CD81 and F-actin into cytoplasmic agglomerates. These findings suggest that in neuronal-like cells CD81 bridges active AKT and actin, promoting the actin remodeling that leads to a motile cell morphology. Further studies on this CD81-mediated mechanism will improve our knowledge on important physiological and pathological processes such as cell migration and differentiation, and tumor metastasis. This work was supported by Fundação para a Ciência e Tecnologia (Portuguese Ministry of Science and Technology), Centro 2020 and Portugal2020, the COMPETE program, QREN, and the European Union (FEDER program) via the Institute for Biomedicine iBiMED UID/BIM/ 04501/2013, fellowship SFRH/BD/90996/2012, project PTDC/CVT-CVT/ 32261/2017, and the support of the LiM facility of iBiMED, a member of the Portuguese Platform of BioImaging (PPBI- POCI-01-0145-FEDER-022122). published

In the developing mammalian cerebral cortex, newly generated neurons migrate toward the pial surface to form a mammalian-specific six-layered cerebral cortex. Genetic studies of human neurological diseases have suggested the involvement of several molecules in cortical neuronal migration. In vivo electroporation is another powerful tool for understanding the molecular mechanisms of neuronal migration. By using these techniques, however, it is difficult to understand molecular basis of time-dependent changes of neuronal morphologies. Here, we introduce a pharmacological approach to cerebral cortical development. Major advantages of the pharmacological approach include the transient suppression of molecules of interest and analyzing time-dependent changes of neuronal morphologies. It also allows us to search molecules regulating neuronal migration with comparative ease. We propose the complementarity between the pharmacological approach and genetics or in vivo electroporation experiments.

Neuronal connectivity in the cortex is determined by the laminar positioning of neurons. An important determinant of laminar positioning is likely to be the control of leading process behavior during migration, maintaining their tips directed toward the pia. In this study, we provide evidence that pial bone morphogenetic protein (Bmp) signaling regulates cortical neuronal migration during cortical layer formation. Specific disruption of pial Bmp ligands impaired the positioning of early-born neurons in the deep layer; further, cell-autonomous inhibition of Smad4, a core nuclear factor mediating Bmp signaling, in the cortical radial glial cells or postmitotic cortical neurons also produced neuronal migration defects that blurred the cortical layers. We found that leading processes were abnormal and that this was accompanied by excess dephosphorylated cofilin-1, an actin-severing protein, in Smad4 mutant neurons. This suggested that regulation of cofilin-1 might transduce Bmp signaling in the migrating neurons. Ectopic expression of a phosphorylation-defective form of cofilin-1 in the late-born wild-type neurons led them to stall in the deep layer, similar to the Smad4 mutant neurons. Expression of a phosphomimetic variant of cofilin-1 in the Smad4 mutant neurons rescued the migration defects. This suggests that cofilin-1 activity underlies Bmp-mediated cortical neuronal migration. This study shows that cofilin-1 mediates pial Bmp signaling during the positioning of cortical neurons and the formation of cortical layers.

The human insula is a key node in a neuronal network which integrates interoceptive stimuli from the own body, and exteroceptive stimuli from the environment, and thus maintains the autonomic, emotional and socio-cognitive homeostasis of the body. In the last years, the insula has come into the focus of attention. Comparative anatomical studies showed that in many species the insula forms the lateral edge of the cortex. Very little is known about the prenatal development of the human insula, which is the first cortical region to mature. The origin of the pyramidal neurons for the insula is a small sector of the proliferating ventricular/subventricular zone at the cortico-striatal boundary (CSB). The CSB contains the radial glia cells, which are stem cells and give rise to a dense fascicle of radial glia processes. This fascicle traverses the external capsule and serves as a migration substrate for the neuroblasts on their way from the CSB into the insula. Around the 10/11th week of gestation, the lateral ventricle and its adjacent structures including the CSB bend in a C-shaped fashion. The insula now develops between a dorsal, fronto-parietal and a ventral, temporal CSB, which provide descending and ascending streams of neuroblasts, respectively, migrating along the radial glia fascicle. As a consequence of the ventricular rotation during ontogenesis, the human insula changes its initial position at the lateral edge of the cortex to its final central location, which reflects its integrative functions in brain activity.

Precise positioning of neurons resulting from cell division and migration during development is critical for normal brain function. Disruption of neuronal migration can cause a myriad of neurological disorders. To investigate the functional consequences of defective neuronal positioning on circuit function, we studied a zebrafish frizzled3a (fzd3a) loss-of-function mutant off-limits (olt) where the facial branchiomotor (FBM) neurons fail to migrate out of their birthplace. A jaw movement assay, which measures the opening of the zebrafish jaw (gape), showed that the frequency of gape events, but not their amplitude, was decreased in olt mutants. Consistent with this, a larval feeding assay revealed decreased food intake in olt mutants, indicating that the FBM circuit in mutants generates defective functional outputs. We tested various mechanisms that could generate defective functional outputs in mutants. While fzd3a is ubiquitously expressed in neural and non-neural tissues, jaw cartilage and muscle developed normally in olt mutants, and muscle function also appeared to be unaffected. Although FBM neurons were mispositioned in olt mutants, axon pathfinding to jaw muscles was unaffected. Moreover, neuromuscular junctions established by FBM neurons on jaw muscles were similar between wildtype siblings and olt mutants. Interestingly, motor axons innervating the interhyoideus jaw muscle were frequently defasciculated in olt mutants. Furthermore, GCaMP imaging revealed that mutant FBM neurons were less active than their wildtype counterparts. These data show that aberrant positioning of FBM neurons in olt mutants is correlated with subtle defects in fasciculation and neuronal activity, potentially generating defective functional outputs.

International audience; Reelin, a glycoprotein of the extracellular matrix, has been the focus of several studies over the years, mostly for its role in cell migration. Here we report the role of this molecule and of its downstream pathways in post-mitotic neurons and how they contribute to neural circuit assembly, refinement and function. Accumulating evidence has pointed at a major role for Reelin in axonal guidance, synaptogenesis and dendritic spine formation. In particular new evidence points at a direct role in axonal targeting and refinement at the target site. In addition, recent advances highlight new functions of Reelin in the modulation of synaptic activity, plasticity and behavior and it directly regulates GABA receptors expression and stability. We discuss these findings in the context of neurodevelopmental disorders. Highlights  Reelin signaling is required for axonal targeting and refinement at the target site.  Reelin signaling regulates dendritogenesis and spine formation in mature neurons.  Reelin modulates GABA receptors expression and stability, pre-and-post-synaptically.  Reelin is important for hippocampal integrity, synaptic plasticity and behavior.