Neuronal guidance genes in health and diseases

Neurons migrate from their birthplaces to the destinations, and extending axons navigate to their synaptic targets by sensing various extracellular cues in spatiotemporally controlled manners. These evolutionally conserved guidance cues and their receptors regulate multiple aspects of neural development to establish the highly complex nervous system by mediating both short- and long-range cell-cell communications. Neuronal guidance genes (encoding cues, receptors, or downstream signal transducers) are critical not only for development of the nervous system but also for synaptic maintenance, remodeling, and function in the adult brain. One emerging theme is the combinatorial and complementary functions of relatively limited classes of neuronal guidance genes in multiple processes, including neuronal migration, axonal guidance, synaptogenesis, and circuit formation. Importantly, neuronal guidance genes also regulate cell migration and cell-cell communications outside the nervous system. We are just beginning to understand how cells integrate multiple guidance and adhesion signaling inputs to determine overall cellular/subcellular behavior and how aberrant guidance signaling in various cell types contributes to diverse human diseases, ranging from developmental, neuropsychiatric, and neurodegenerative disorders to cancer metastasis. We review classic studies and recent advances in understanding signaling mechanisms of the guidance genes as well as their roles in human diseases. Furthermore, we discuss the remaining challenges and therapeutic potentials of modulating neuronal guidance pathways in neural repair.

SCN2A mutation in an infant with Ohtahara syndrome and neuroimaging findings: expanding the phenotype of neuronal migration disorders

Neuronal migration disorders (NMDs) are a heterogeneous group of conditions caused by the abnormal migration of neuroblasts in the developing brain and nervous system, resulting in severe developmental impairment, intractable epilepsy and intellectual disability (Spalice et al. 2009). To date, many genes have been identified as the leading cause of migration defects, i.e. agyria/pachygyria, polymicrogyria, heterotopias, agenesis of the corpus callosum and agenesis of the cranial nerves (Spalice et al. 2009). Here, we present a patient with early infantile epileptic encephalopathy (Ohtahara syndrome) with seizure onset on the first dayof life, severe developmental delay and an abnormal brain MRI with excessive folding of small, fused gyri and bilateral perisylvian polymicrogyria, suggestive of neuronal migration disorder. To clarify the unknown aetiology, we conducted whole-exome sequencing, which detected a de novo missense variant (c.5308A>T; p.(Met1770Leu)) in the SCN2A gene. This is a report of SCN2A gene variant identified in a patient with neuronal migration disorder which could further expand the phenotypic spectrum of these genetic disorders.

Expression of neuronal migration-related factors and the spatial learning and memory of rats prenatally exposed to tritiated water / 中华放射医学与防护杂志

Objective To study the expression of neuronal migration-related factors and spatial learning and memory of rats exposed to tritiated water (HTO).Methods Hippocampal neural cells from newborn Sprague-Dawley (SD) rats at postnatal 24 h were primarily cultured in DMEM/F12 medium with 20％ of fetal bovine serum for 6 days,followed by subjection to tritiated water (HTO) at concentrations of 3.7× 102,3.7×103,3.7 × 104,3.7 × 105,3.7× 106 Bq/ml for 24 h,respectively.Western blot and RT-qPCR were used to determine the expression levels of F-actin,α-tubulin,tau,AP2,BDNF mRNA and Reelin mRNA.16 pregnant SD rats at embryonic (E) day 14 were randomly divided into the tested and control groups (8 rats/ each group).The tested rats were injected with body fluid of HTO (3.7× 106 Bq/g) intraperitoneally,while the saline as the control.Morris water maze (MWM) was employed for the spatial learning and memory of rats.Results Compared to the control cells,HTO caused a significant downregulation of expressions of cytoskeletal proteins [F-actin (t =8.898-19.896,P＜ 0.05),α-tubulin (t=3.261-7.900,P＜0.05),tau (t=2.274-5.003,P＜0.05),and MAP2 (t=2.274-5.003,P＜0.05)] and mRNA of BDNF (t=3.580-19.792,P＜0.05) and Reelin (t=3.240-39.692,P＜0.05)in the tested neural cells in a dose-dependent manner.In addition,the escape latency of irradiated offsprings was significantly prolonged (t =-2.563,P＜0.05),the time for offsprings to cross through target quadrant was markedly reduced (t=3.214,P＜0.05),and the swimming time in the platform quadrant of irradiated offsprings were obviously shortened (t =3.874,P＜0.05) in the MWM trial.Conclusions The results indicate that HTO irradiation in utero downregulates the expressions of neuron migration-related factors and induces brain dysfunction,which may shed a light on a mechanism of the radiation-induced brain impairment.

Expression of neuronal migration-related factors and the spatial learning and memory of rats prenatally exposed to tritiated water / 中华放射医学与防护杂志

Objective@#To study the expression of neuronal migration-related factors and spatial learning and memory of rats exposed to tritiated water (HTO).@*Methods@#Hippocampal neural cells from newborn Sprague-Dawley(SD) rats at postnatal 24 h were primarily cultured in DMEM/F12 medium with 20% of fetal bovine serum for 6 days, followed by subjection to tritiated water(HTO) at concentrations of 3.7×102, 3.7×103, 3.7×104, 3.7×105, 3.7×106 Bq/ml for 24 h, respectively. Western blot and RT-qPCR were used to determine the expression levels of F-actin, α-tubulin, tau, AP2, BDNF mRNA and Reelin mRNA. 16 pregnant SD rats at embryonic (E) day 14 were randomly divided into the tested and control groups (8 rats/ each group). The tested rats were injected with body fluid of HTO (3.7×106 Bq/g) intraperitoneally, while the saline as the control. Morris water maze (MWM) was employed for the spatial learning and memory of rats.@*Results@#Compared to the control cells, HTO caused a significant downregulation of expressions of cytoskeletal proteins [F-actin (t=8.898-19.896, P<0.05), α-tubulin (t=3.261-7.900, P<0.05), tau (t=2.274-5.003, P<0.05), and MAP2 (t=2.274-5.003, P<0.05)] and mRNA of BDNF(t=3.580-19.792, P<0.05) and Reelin (t=3.240-39.692, P<0.05) in the tested neural cells in a dose-dependent manner. In addition, the escape latency of irradiated offsprings was significantly prolonged (t=-2.563, P<0.05), the time for offsprings to cross through target quadrant was markedly reduced (t=3.214, P<0.05), and the swimming time in the platform quadrant of irradiated offsprings were obviously shortened (t=3.874, P<0.05) in the MWM trial.@*Conclusions@#The results indicate that HTO irradiation in utero downregulates the expressions of neuron migration-related factors and induces brain dysfunction, which may shed a light on a mechanism of the radiation-induced brain impairment.

Hemiplegia Hemiconvusion Hemiatrophy Syndrome-A Case Report

Neuronal migration disorder is a rare cause of seizure, weakness and developmental delay 1. Individuals with smaller, unilateral clefts may be paralyzed on one side of the body 2. Outcome and presentation of schizencephaly are variable, but it typically presents with seizures ,hemiparesis,and developmental delay. Here we report a case of open lip schizencephaly presenting as Hemiplegia Hemiconvusion Hemiatrophy Syndrome.

Coactosin-like protein 1 inhibits neuronal migration during mouse corticogenesis

Coactosin-like protein 1 (Cotl1), a member of the actin-depolymerizing factor (ADF)/cofilin family, was first purified from a soluble fraction of Dictyostelium discoideum cells. Neuronal migration requires cytoskeletal remodeling and actin regulation. Although Cotl1 strongly binds to F-actin, the role of Cotl1 in neuronal migration remains undescribed. In this study, we revealed that Cotl1 overexpression impaired migration of both early- and late-born neurons during mouse corticogenesis. Moreover, Cotl1 overexpression delayed, rather than blocked, neuronal migration in late-born neurons. Cotl1 expression disturbed the morphology of migrating neurons, lengthening the leading processes. This study is the first to investigate the function of Cotl1, and the results indicate that Cotl1 is involved in the regulation of neuronal migration and morphogenesis.

Clinical Characteristics and Efficacy Analysis of Children with Cerebral Palsy and Neuronal Migration Disorders / 中国康复理论与实践

@#Objective To discuss the clinical characteristics and efficacy analysis of children with cerebral palsy and neuronal migration disorders (NMD) by retrospective analysis. Methods From June, 2005 to June, 2015, 32 children with cerebral palsy and NMD were en-rolled as NMD group, while 60 children with cerebral palsy with periventricular leukomalacia (PVL) as PVL group. Both groups received comprehensive rehabilitation for three months. Their clinical classification, complications of epilepsy or epileptiform discharges, the score of Gross Motor Function Measure (GMFM), and development quotient (DQ) were compared, as well as the follow-up results of six months. Results There was significant difference in the clinical classification of cerebral palsy between two groups (χ2=24.529, P<0.001). The inci-dence of epilepsy and epileptiform discharges was higher in NMD group than in PVL group (χ2>4.605, P<0.05). After treatment, the score of GMFM improved with time in both groups (Ftime=6.850, P=0.010), and was significantly lower in NMD group than in GMFM group (Fgroup=29.885, P<0.001);the scores of DQ in all the functional areas improved with time in both groups (Ftime>25.041, P<0.001), and were signifi-cantly lower in NMD group than in GMFM group (Fgroup>32.347, P<0.001). Conclusion Children with cerebral palsy and NMD are charac-terized by mental retardation, epilepsy and spastic hemiplegia, and poor outcome.

miR-130b accelerates the neuronal migration in the developing embryonic mice cortex / 基础医学与临床

Objective To study the effects of miR-130b on the neuronal migration in the developing embryonic mice cortex.Methods Pregnancy E15.5 mice were selected and plasmid of miR-130b was injected into the lateral ventricle of the embryonic brain.Two days after eletroporation,murine embryos were collected and cut into frozon coronal slices,then surveyed the neuronal migration under the fluorescence microscope.Results The neuronal migration rates were higher in miR-130b overexpression embryonic cortex,of which 75.1％ eletroporated neurons migrated into MZ,compared with the 22.1％ in control group.On the contrary,only 7.9％ eletroporated neurons stayed in the VZ/ SVZ in the experimental group,compared with the 69.3％ in control group.Conclusions miR-130b accelerates the neuronal migration in the developing embryonic mice cortex,its regulational role is worth studying.

NS4A protein of Zika virus influences the neuronal migration of mouse cortex / 基础医学与临床

Objective To determine the effect of NS3 and NS4A proteins of Zika virus on the neuronal migration in vivo.Methods To identify the coding sequence of NS3 and NS4A,the genome of Zika SZ01 was sequenced by rapid amplification of cDNA ends (RACE) and reverse-transcription PCR,then NS3 and NS4A was constructed in pCIG vector fused with Flag-tag to express these proteins.And then these plasmids was transfected into the embryo brain of E13.5 mice by in utero electroporation,the distribution of the cells which express these proteins in the cortex was detected by Flag,eGFP and TBR1 fluorescence in E18.5 mice through immunohistochemistry so as to assess the influence of viral proteins on the neuronal migration of mouse cortex.Results 1) Sequence results showed that the amino acid sequence of NS4A is consistent with NCBI data,while NS3 has 1 amino acid mutant.2) As the fluorescence of Flag and eGFP can co-localization,the eGFP fluorescence signal marks the cells that have expressed these virus proteins in cortex.3) TBR1 fluorescence shows the distribution of the cells that express NS4A in vivo are significantly different from pCIG control and NS3 (P＜0.001).Conclusions The NS4A protein of Zika virus may affect the neuronal migration in vivo.

Function of Znf804a in neuronal migration, proliferation and differentiation during mice brain development / 中国心理卫生杂志

Objective:To explore the function of Znf804a during brain development by using mouse model.Methods:The shRNA of Znf804a (shZnf804a) and control (pSUPER) plasmids were introduced into ventricular zone of ICR (Institute of Cancer Research) mice at E14.5 (three mice in each group) by using in utero electroporation.The speed of migration was evaluated by comparing the proportions of neuron in cortical plate (CP) zone.The proliferation speed was evaluated by comparing the diameters of neurospheres formed by neuron progenitor cells.The differentiation speed was evaluated by comparing the proportions of Nestin staining positive cells in neuron progenitor cells.Results:The proportion of neurons in CP zone was lower in shZnf804a group than in controls(11.8％ vs.75.4％,P ＜ 0.001).The diameter of neurospheres formed by neuron progenitor cells was bigger in shZnf804a group than in controls (295μm vs.172μm,P ＜0.01).The proportion of Nest in staining positive cells in neuron progenitor cells was larger in shZnf804a group than in controls (31.5％ vs.9.6％,P ＜0.01).Conclusion:It suggests that the migration speed of neurons in shZnf804a is lower than that in controls,the proliferation speed is higher than that in controls,and the differentiation speed is lower than that in controls.These results indicate that Znf804a may play an important role in the development of mouse brain.

Heterotopía nodular periventricular, objetivo quirúrgico en epilepsia refractaria al manejo farmacológico / Periventricular Nodular Heterotopia, Surgical Goal in Drug-Resistant Epilepsy / Heterotopia Nodular Periventricular, objetivo cirúrgico em epilepsia refratária ao manejo farmacológico

Introducción: La heterotopía neuronal es un defecto de la migración en el cual estas células no completan su desplazamiento hacia la corteza. La forma más comúnmente reportada es la heterotopía nodular periventricular, caracterizada por conglomerados neuronales que se ubican adyacentes a las paredes de los ventrículos laterales. Hasta el 90% de los pacientes con esta condición presentan epilepsia en algún momento de la vida y una gran proporción de ellos serán refractarios al manejo farmacológico. Esto hace necesario un adecuado abordaje diagnóstico que busque establecer qué pacientes se beneficiarían de resección quirúrgica de la lesión, que en la mayoría de los casos ofrece una alta tasa de control de crisis. Desarrollo: Se presenta un recorrido desde la práctica por los aspectos con mayor relevancia en cuanto a la fisiopatología, manifestaciones clínicas, abordaje diagnóstico y terapéutico de la heterotopía nodular periventricular, con el fin de explorar el rol de esta condición como causante de epilepsia refractaria. Conclusión: La epilepsia refractaria al tratamiento condiciona de manera significativa la calidad de vida de los pacientes. Una entidad frecuentemente asociada a esto es la heterotopía nodular periventricular, la cual debe ser correctamente abordada por el equipo médico tratante procurando un diagnóstico oportuno y definiendo qué pacientes se benefician del manejo quirúrgico. De esta manera, se impacta positivamente la calidad de vida de estos sujetos y de sus cuidadores.

Introduction: Neuronal heterotopia is a migration disorder in which these cells do not complete their movement toward the cerebral cortex. Periventricular nodular heterotopia is the most frequently reported form, characterized by neuronal conglomerates adjacent to the lateral ventricles walls.About 90 % of patients with this condition suffer epilepsy at some point in their lives and the major proportion of them will be resistant to pharmacologic treatment. This makes an appropriate diagnostic approach necessary in order to determine which patients would benefit from surgical resection of the lesion, which in most cases offers a high rate of crisis control. Development: This article presents a review of the most important topics approached from the practice of periventricular nodular heterotopia pathophysiology, clinical features, diagnosis and therapy. It is aimed at exploring the role of this condition as a cause of intractable epilepsy. Conclusion: Pharmacologic treatment for resistant epilepsy will have a severe impact on patient's quality of life. Periventricular nodular heterotopia is frequently associated to this condition, which must be successfully approached by the medical team attempting to an opportune diagnosis and defining which patients would benefit from surgical management. This positively impacts the quality of life of these patients and their caregivers.

Introdução: A heterotopia neuronal é um defeito da migração no qual estas células não completam seu deslocamento ao córtex. A forma mais comunmente reportada é a heterotopia nodular periventricular, caracterizada por conglomerados neuronais que se localizam adjacentes às paredes dos ventrículos laterais. Até o 90% dos pacientes com esta condição apresentam epilepsia em algum momento da vida e uma grande proporção deles, serão refratários ao manejo farmacológico. Isto faz necessária uma adequada abordagem diagnóstica, buscando estabelecer quais pacientes se beneficiariam de ressecção cirúrgica da lesão, que na maioria dos casos oferece uma alta taxa de controle de crises. Desenvolvimento: Se apresenta um recorrido desde a prática pelos aspectos com maior relevância em quanto à fisiopatologia, manifestações clínicas, abordagem diagnóstica e terapêutica da heterotopia nodular periventricular. Com o fim de explorar o rol desta condição como causador de epilepsia refratária. Conclusão: A epilepsia refratária ao tratamento condiciona de maneira significativa à qualidade de vida dos pacientes. Uma entidade frequentemente associada a isto é a heterotopia nodular periventricular, a qual deve ser corretamente abordada pela equipe médica tratante procurando um diagnóstico oportuno e definindo quais pacientes se beneficiam de manejo cirúrgico. Desta forma impacta-se positivamente a qualidade de vida destes sujeitos e de seus cuidadores.

Advances in gray matter heterotopia in children / 国际儿科学杂志

Gray matter heterotopias,which can be classified into subependymal heterotopia,subcortical heterotopia,band heterotopia and mixed heterotopia,belongs to neuronal migration disorders.Any factors including physical or chemical factors,biological factors and genetical factors that occur during neuronal migration phase can lead to gray matter heterotopias.The latest studies have revealed many genes are involved in the pathogenesis of gray matter heterotopias,especially in subependymal heterotopia and band heterotopia with their own characteristics.The main clinical disorders in pediatric heterotopias include developmental delay,epilepsy and motor disturbance.The diagnosis of the disease is made through neuroimaging examinations especially magnetic resonance imagings.The advanced magnetic techniques like magnetic resonance spectroscopy and functional magnetic resonance can be helpful in the final diagnosis.

Hirschsprung’s Disease with Congenital Hypothyroidism.

We report a female newborn baby who presented with vomiting and abdominal distension on day 21 of life. Examination revealed facial puffiness, open posterior fontanelles, dry skin, cold peripheries and prominent abdominal veins with visible peristalsis. Barium enema revealed dilated proximal colon, empty rectum, funnel like transition zone between proximal dilated and distal constricted bowel. Serum TSH level was >150 μIU/mL. Biopsy revealed aganglionic segment suggesting Hirschsprung’s disease, an unusual association with congenital hypothyroidism.

Migration and maturation pattern of fetal enteric ganglia: A study of 16 cases.

Aims: To study the migration and developmental pattern of ganglion cells in fetuses aged 9-21 weeks, and to document whether the migration was occurring circumferentially equally in the entire axis or if there were discrepancies in different portions at the same level. Settings and Design: The hypothesis regarding the pathogenesis of Hirschsprung's disease mainly revolves around two schools. One is the single gradient migration of ganglia and the other is a dual gradient migration theory. Understanding the embryological development of enteric ganglia is necessary to study the pathogenesis of intestinal innervation disorders. Materials and Methods: We studied the development of intestinal ganglia in fetuses aged 9-21 weeks. Serial longitudinal sections from the colon were studied, the first one including the squamo-columnar junction, for the presence and the nature of ganglion cells with Hematoxylin and Eosin, and neurone-specific enolase immunostaining. Transverse sections from proximal gut were studied in a similar fashion. Thus, we evaluated the migration pattern as well as the nature of ganglia in the fetuses. We also measured the length of distal aganglionic segment in these growing fetuses. Results: We noted that ganglion cells appear first in the myenteric plexus followed by deep and superficial submucous plexus. We also found evidences in favor of dual migration theory, and the distal aganglionic segment varies around the circumference of the rectal wall. Conclusions: We got evidences in support of a dual migration pattern of intestinal ganglion cells. The level of distal aganglionic segments when measured from squamo-columnar junction varied with the age of gestation and the length was incongruous. The description of distal aganglionic segment may help surgeons while taking biopsies or during operative procedures.

Esquizencefalia de labio cerrado bilateral: a propósito de un caso / Schizencephaly of bilateral closed lip: speaking of one case

La esquizencefalia es un desorden de la migración neuronal, caracterizada por hendiduras de sustancia gris en los hemisferios cerebrales que se extienden desde la superficie pial a los ventrículos laterales. Esta patología es el resultado final de una amplia variedad de factores genéticos, tóxicos, metabólicos y de agentes infecciosos que ocurren durante un período crítico del desarrollo cerebral. Esta malformación puede ser unilateral o bilateral y puede ser dividida en dos subtipos: de ¨labios cerredos" o tipo I, o de "Labios abierto" o tipo II. Presentamos el caso de una paciente demenina de 37 años de edad con epilepsia y hallazgos neurorradiológicos de esquizencefalia de "labios cerrados" bilateral

Schizencephaly is a rare developmental of neuronal migration, characterized by congenital clefts spanning the cerebral hemisphere from the pial surface to the lateral ventricle and lined by cortical gray matter. The lesion is the final result of a variety of etiologies including genetic, toxic, metabolic and infectious agents during a critical period of the development of the brain. This malformation can be unilateral or bilateral and may be divided in two subtypes: "closed tips" or type I and "open tips" or type II. We present 37 years old female patient with epilepsy and neuroradiological findings of bilateral "closed lips" schizencephaly

Normal neuronal migration / Migración neural normal

Ontogenesis of both central and peripheral nervous systems depends on basic, molecular and cellular mechanisms of the normal neuronal migration. Any deviation leads to neural malformations. All neural cells and structures derive from the neural ectoderm, which under the influence of the notochord and the molecules Noggin and Chordin, is transformed consecutively into neural plate, neural groove, neural tube and primary vesicles. Of the latter, the most rostral, the prosencephalon, two vesicles are bilaterally generated, the telencephalon and in the middle, the unpaired diencephalons. The telencepahlic vesicles generate the cerebral hemispheres and the lateral ventricles; the latter constitutes the main source of progenitor neuroepithelial cells (NEC) in the subventricular zone. The NEC massively migrates to constitute the cerebral cortex and other hemispheric structures in the telencephalon and diencephalon. The NEC expresses a broad repertory of markers: BLBP, GLAST, vimentin, tenascin, S100-3 and, in primates GFAP; in a sequential order the NEC form the first cortical layer formed by the marginal zone and the subplate. The marginal zone harbors the Cajal-Retzius reelin positive neurons and reelin negative neurons. Reelin, besides signaling stop to migrating neurons, also participates in ordering the cortical layers; it is known that in mutant mice lacking reelin cortical layers are disrupted. Genetic studies indicate that ApoER2, Vldr (both reelin receptors) and Dab1, reelin signaling adaptor protein, enter into a common pathway leading Dab1 to phosphorylation in migrating neurons. Cortical pyramidal neurons generate at germinal zone; interneurons generate both in Vz and SVZ in medial ganglionic eminence and caudal GE. Two types of neuronal migration coexist, radial and tangential. In radial migration, the neurons move perpendicular to marginal zone and radial glia serves as a scaffold to migrating cells; in the tangential way, neurons migrate in parallel to brain surface guided by semaphorins, neuropilins, cell adhesion molecules, neuregulins, chemokines and the slit and robo families of attractant and repellent molecules. The migratory cycle of neurons involves leading process dynamics and somal translocation, which involves the movement of perinuclear material, organelles and nucleus. Leading process stability depends on the microtubular array that links the leading edge of the cell with the soma. The centrosome is a microtubule center to control microtubule polymerization. In radially migrating neurons, the centrosome establishes a link between centrioles and nuclear membrane. The effective neuronal migration is only completed by translocation of the cell soma, which occurs with cytoplasmic dilatation, and then the centrosome and Golgi apparatus approach it, finally nucleus advances to the cytoplasmic dilatation. Movement of centrosome and nucleus depends on integrity of a microtubule network. Most of the microtubules surrounding the nucleus are tyrosinated, making them dynamic; microtubules at the anterior pole of the nucleus, near the centrosome, are acetylated. Once neurons reach their final destination, they need to cancel the migratory program and differentiate. The mechanisms are unknown; possibly early patterns of activity in the target region could influence. Ca2+ influx is a proposed mechanism for halting migration.

La ontogenia de los Sistemas Nervioso Central y Nervioso Periférico depende de procesos como la proliferación, diferenciación y migración neuronal, entre otros. Cualquier desviación resulta en malformaciones. Las estructuras y células nerviosas derivan del ectodermo, la notocorda induce la formación de la placa neural mediante la secreción de las moléculas Noggin y Chordin; posteriormente la placa neural se convierte en surco y tubo neurales. Una vez que el tubo neural está formado, las células neuroepiteliales (CNE), futuras neuronas y glía, en la zona subventricular migran masivamente para constituir la corteza cerebral y otras estructuras. Las CNE, al ser células gliales, expresan múltples marcadores: BLBP, GLAST, vimentin, tenascin, S1 00p y en primates GFAP Las CNE forman la primera capa cortical, también llamada preplato. Las siguientes divisiones celulares darán origen a la zona marginal y al subplato. Las subsecuentes neuronas que arriban al subplato desplazan a las anteriores de modo que en las capas superficiales se encuentran las últimas neuronas que llegaron. La capa marginal o capa I contiene células de Cajal-Retzius inmunorreactivas a reelin y neuronas reelin-negativas situadas más profundamente. La proteína reelin, además de servir como señal de alto a las neuronas migratorias, también interviene en el orden de la laminación cortical, la cual es desordenada en los ratones que carecen de reelin. No se conoce en su totalidad el mecanismo molecular mediante el cual reelin regula los procesos antes mencionados. Hasta el momento se conoce que ApoER2, Vldlr (ambos receptors de reelin) y Dab1, proteína adaptadora en la señalización por reelin, participan en una vía común que lleva a la fosforilación de Dab1 en las neuronas en migración. Las neuronas piramidales corticales se generan en el telencéfalo dorsal, mientras que las interneuronas se generan en la zona y subzona ventriculares del telencéfalo ventral, en las bien definidas subdivisiones de la eminencia gangliónica (EG): lateral, medial y caudal. La migración neuronal puede ser radial o tangencial; la migración radial emplea a la glía radial mientras que en la tangencial las neuronas migran paralelamente a la superficie cortical. En los dos tipos hay formación de neuritas, translocación somática y núcleocinesis. Varios factores participan en la migración tangencial: semaforinas, neuropilinas, moléculas de adhesion celular, neuregulinas, quimiocinas y moléculas atrayentes y repelentes de las familias slit y robo. El ciclo migratorio de las neuronas incluye la translocación del soma con movilización de material perinuclear, organelos y del núcleo. Así mismo, dicho ciclo aparece con morfología bien definida en una variedad de neuronas lo que refleja adaptación a ambientes específicos. De tal modo que las claves guías influyen en la frecuencia y orientación de la emergencia dendrítica, que a su vez permite a las neuronas migrantes cambiar de dirección sin reorientar las dendritas preexistentes. La estabilidad del mecanismo depende de la organización microtubular que asocia el borde celular con el soma; ya que el sistema de microtúbulos apoya dicho mecanismo y también permite el flujo de vesículas. En las células animales el centrosoma es el centro que organiza el citoesqueleto, la polimerización, el arreglo de los microtúbulos perinucleares y establece el contacto de los centriolos con la membrana nuclear. En la migración radial el movimiento hacia delante de los centriolos deforma el conjunto perinuclear de microtúbulos. Se debe a la elasticidad de ese conjunto microtubular y sus proteínas motoras asociadas al desplazamiento del núcleo. La nucleocinesis o movimiento del núcleo determina la dirección del movimiento nuclear, la migración neuronal efectiva sólo se completa por la translocación subsecuente del soma, lo cual ocurre por la dilatación del citoplasma y el movimiento del centrosoma y del aparato de Golgi hacía el mecanismo; finalmente el núcleo avanza e invade la dilatación del citoplasma. El movimiento del centrosoma y del núcleo depende de la integridad de la red microtubular y de las modificaciones posttranscripción. La mayoría de los micotúbulos perinucleares están tirosinados, lo cual los hace extremadamente dinámicos; en cambio, los microtúbulos del polo anterior del núcleo, vecinos del centrosoma, están acetilados y por ende más estables. Se ha dicho que los microtúbulos perinucleares se hallan conectados con el centrosoma que en sí es el centro que los organiza. Además, se han descrito otras proteínas asociadas con la polaridad celular que desempeñan un papel esencial en la coordinación del movimiento del centrosoma y del núcleo en cada ciclo migratorio. Finalmente, una vez que las neuronas alcanzan su posición definitiva, requieren cancelar el programa migratorio y continuar su diferenciación hasta alcanzar las características morfológicas y funcionales que les corresponden.

Bilateral Frontal Polymicrogyria: An Autopsy Case Report

Bilateral frontal polymicrogyria is a recently recognized syndrome characterized by symmetric polymicrogyria of both frontal lobes that presents with delayed motor and language development, spastic quadriparesis, and variable mental retardation. However, the postmortem findings of this syndrome are not fully elaborated. Here we describe an autopsy case of bilateral frontal polymicrogyria in a male fetus delivered at 22 weeks gestation due to extensive chorioamnionitis. The microscopic findings included a thinned cortical plate with fair neuronal maturation. There were no signs of neuronal damage and the white matter was unremarkable.

Migratory defect of mesencephalic dopaminergic neurons in developing reeler mice / 대한해부학회지

Reelin, an extracellular glycoprotein has an important role in the proper migration and positioning of neurons during brain development. Lack of reelin causes not only disorganized lamination of the cerebral and cerebellar cortex but also malpositioning of mesencephalic dopaminergic (mDA) neurons. However, the accurate role of reelin in the migration and positioning of mDA neurons is not fully elucidated. In this study, reelin-deficient reeler mice exhibited a significant loss of mDA neurons in the substantia nigra pars compacta (SNc) and a severe alteration of cell distribution in the retrorubal field (RRF). This abnormality was also found in Dab1-deficinet, yotari mice. Stereological analysis revealed that total number of mDA neurons was not changed compared to wild type, suggesting that the loss of mDA neurons in reeler may not be due to the neurogenesis of mDA neurons. We also found that formation of PSA-NCAM-positive tangential nerve fibers rather than radial glial fibers was greatly reduced in the early developmental stage (E14.5) of reeler. These findings provide direct evidence that the alteration in distribution pattern of mDA neurons in the reeler mesencephalon mainly results from the defect of the lateral migration using tangential fibers as a scaffold.

Control of neuronal migration through rostral migration stream in mice / 대한해부학회지

During the nervous system development, immature neuroblasts have a strong potential to migrate toward their destination. In the adult brain, new neurons are continuously generated in the neurogenic niche located near the ventricle, and the newly generated cells actively migrate toward their destination, olfactory bulb, via highly specialized migratory route called rostral migratory stream (RMS). Neuroblasts in the RMS form chains by their homophilic interactions, and the neuroblasts in chains continually migrate through the tunnels formed by meshwork of astrocytes, glial tube. This review focuses on the development and structure of RMS and the regulation of neuroblast migration in the RMS. Better understanding of RMS migration may be crucial for improving functional replacement therapy by supplying endogenous neuronal cells to the injury sites more efficiently.

Immunohistochemical study of acute effects of ethanol on midbrain of wistar rats associated with the date of birth of neurons in encephalon / Estudio inmunohistoquímico de los efectos agudos del etanol sobre el mesencéfalo de ratas wistar asociado con la fecha de formación de neuronas en el cerebro

The verification of the acute effects of ethanol on the midbrain, which neurons are mainly formed in E14, will ratify if the acute effects of ethanol are associated, in terms of prevalence, to the date of birth of neurons in certain regions of the brain. The aim of this study was to determine the effects of acute exposure to ethanol on the neuronal density of the midbrain and to associate these results with acute effects of ethanol in other regions of the brain under the same conditions. The rats were treated with intraperitoneal ethanol during one day (E12) and 1h after the last ethanol injection was applied to BrdU. The animals were sacrificed; the brains were removed and sectioned. The sections were treated with DAB for the BrdU revelation, the slides were stained with safranin for one group and another group was stained with H & E. The effects of acute injection of ethanol in E12 on the midbrain were not detected in this study. Data from literature suggest that the deleterious action of acute ethanol consumption only occur if the drug is injected at times near the beginning of the migration of neurons in that particular region of the brain.

La verificación de los efectos agudos del etanol sobre el mesencéfalo, cuyas neuronas se forman principalmente en la E14, puede ratificar si los efectos agudos del etanol están asociados, en términos de prevalencia, a la fecha de nacimiento de neuronas en ciertas regiones del cerebro. El objetivo de este estudio fue determinar los efectos de la exposición aguda al etanol sobre la densidad neuronal del mesencéfalo y asociar estos resultados con los efectos agudos de etanol en otras regiones del cerebro bajo las mismas condiciones. Las ratas fueron tratadas con etanol intraperitoneal durante un día (E12) y 1h después de la última inyección de etanol fue aplicado BrdU. Los animales fueron sacrificados, los cerebros fueron removidos y seccionados. Las secciones fueron tratados con DAB para la revelación de BrdU, las secciones fueron teñidas con safranina para un grupo y otro grupo se tiñeron con H&E. Los efectos agudos de la inyección de etanol en E12 sobre el mesencéfalo no fueron detectados en este estudio. Los datos de la literatura sugieren que los efectos deletéreos del consumo agudo de etanol sólo se producen si la droga se inyecta en etapas cercanas al comienzo de la migración de las neuronas en esa región particular del cerebro.