The mouse Wnt/PCP protein Vangl2 is necessary for migration of facial branchiomotor neurons, and functions independently of Dishevelled

Glasco, D.M.,Sittaramane, V.,Bryant, W.,Fritzsch, B.,Sawant, A.,Paudyal, A.,Stewart, M.,Andre, P.,Cadete Vilhais-Neto, G.,Yang, Y.,Song, M.R.,Murdoch, J.N.,Chandrasekhar, A. Academic Press 2012 Developmental Biology Vol.369 No.2

During development, facial branchiomotor (FBM) neurons, which innervate muscles in the vertebrate head, migrate caudally and radially within the brainstem to form a motor nucleus at the pial surface. Several components of the Wnt/planar cell polarity (PCP) pathway, including the transmembrane protein Vangl2, regulate caudal migration of FBM neurons in zebrafish, but their roles in neuronal migration in mouse have not been investigated in detail. Therefore, we analyzed FBM neuron migration in mouse looptail (Lp) mutants, in which Vangl2 is inactivated. In Vangl2<SUP>Lp/+</SUP> and Vangl2<SUP>Lp/Lp</SUP> embryos, FBM neurons failed to migrate caudally from rhombomere (r) 4 into r6. Although caudal migration was largely blocked, many FBM neurons underwent normal radial migration to the pial surface of the neural tube. In addition, hindbrain patterning and FBM progenitor specification were intact, and FBM neurons did not transfate into other non-migratory neuron types, indicating a specific effect on caudal migration. Since loss-of-function in some zebrafish Wnt/PCP genes does not affect caudal migration of FBM neurons, we tested whether this was also the case in mouse. Embryos null for Ptk7, a regulator of PCP signaling, had severe defects in caudal migration of FBM neurons. However, FBM neurons migrated normally in Dishevelled (Dvl) ½ double mutants, and in zebrafish embryos with disrupted Dvl signaling, suggesting that Dvl function is essentially dispensable for FBM neuron caudal migration. Consistent with this, loss of Dvl2 function in Vangl2<SUP>Lp/+</SUP> embryos did not exacerbate the Vangl2<SUP>Lp/+</SUP> neuronal migration phenotype. These data indicate that caudal migration of FBM neurons is regulated by multiple components of the Wnt/PCP pathway, but, importantly, may not require Dishevelled function. Interestingly, genetic-interaction experiments suggest that rostral FBM neuron migration, which is normally suppressed, depends upon Dvl function.

The SH2 domain is crucial for function of Fyn in neuronal migration and cortical lamination

( Xi Lu ),( Xin De Hu ),( Ling Zhen Song ),( Lei An ),( Ming Hui Duan ),( Shu Lin Chen ),( Shan Ting Zhao ) 생화학분자생물학회 2015 BMB Reports Vol.48 No.2

Neurons in the developing brain form the cortical plate (CP) in an inside-out manner, in which the late-born neurons are located more superficially than the early-born neurons. Fyn, a member of the Src family kinases, plays an important role in neuronal migration by binding to many substrates. However, the role of the Src-homology 2 (SH2) domain in function of Fyn in neuronal migration remains poorly understood. Here, we demonstrate that the SH2 domain is essential for the action of Fyn in neuronal migration and cortical lamination. A point mutation in the Fyn SH2 domain (FynR176A) impaired neuronal migration and their final location in the cerebral cortex, by inducing neuronal aggregation and branching. Thus, we provide the first evidence of the Fyn SH2 domain contributing to neuronal migration and neuronal morphogenesis. [BMB Reports 2015; 48(2): 97-102]

Gintonin influences the morphology and motility of adult brain neurons via LPA receptors

Do-Geun Kim,Hyeon-Joong Kim,Sun-Hye Choi,Sung Min Nam,Hyoung-Chun Kim,Hyewhon Rhim,Ik-Hyun Cho,Man Hee Rhee,Seung-Yeol Nah 고려인삼학회 2021 Journal of Ginseng Research Vol.45 No.3

Background: Gintonin is an exogenous ginseng-derived G-protein-coupled lysophosphatidic acid (LPA) receptor ligand. LPA induces in vitro morphological changes and migration through neuronal LPA1 receptor. Recently, we reported that systemic administration of gintonin increases blood-brain barrier (BBB) permeability via the paracellular pathway and its binding to brain neurons. However, little is known about the influences of gintonin on in vivo neuron morphology and migration in the brain. Materials and methods: We examined the effects of gintonin on in vitro migration and morphology using primary hippocampal neural precursor cells (hNPC) and in vivo effects of gintonin on adult brain neurons using real time microscopic analysis and immunohistochemical analysis to observe the morphological and locational changes induced by gintonin treatment. Results: We found that treating hNPCs with gintonin induced morphological changes with a cell rounding following cell aggregation and return to individual neurons with time relapses. However, the in vitro effects of gintonin on hNPCs were blocked by the LPA1/3 receptor antagonist, Ki16425, and Rho kinase inhibitor, Y27632. We also examined the in vivo effects of gintonin on the morphological changes and migration of neurons in adult mouse brains using anti-NeuN and -neurofilament H antibodies. We found that acute intravenous administration of gintonin induced morphological and migrational changes in brain neurons. Gintonin induced some migrations of neurons with shortened neurofilament H in the cortex. The in vivo effects of gintonin were also blocked by Ki16425. Conclusion: The present report raises the possibility that gintonin could enter the brain and exert its influences on the migration and morphology of adult mouse brain neurons and possibly explains the therapeutic effects of neurological diseases behind the gintonin administration.

Coactosin-like protein 1 inhibits neuronal migration during mouse corticogenesis

Guohong Li,Yupeng Yin,Jiong Chen,Yanle Fan,Juhong Ma,Yingxue Huang,Chen Chen,Pengxiu Dai,Shulin Chen,Shanting Zhao 대한수의학회 2018 Journal of Veterinary Science Vol.19 No.1

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.

Migratory defect of mesencephalic dopaminergic neurons in developing reeler mice

Woo-Young Kang,Sung-Soo Kim,Sung-Kuk Cho,Soyeon Kim,Haeyoung Suh-Kim,Young-Don Lee 대한해부학회 2010 Anatomy & Cell Biology Vol.43 No.3

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.

신경세포 이주 및 조직화 장애의 임상상과 신경 방사선학적 소견에 대한 연구

김정호(Jeong-Ho Kim),고태성(Tae-Sung Ko),문형남(Hyung-Nam Moonm),최충곤( Choong-Gon Choi) 대한소아신경학회 1996 대한소아신경학회지 Vol.3 No.2

연구 배경 : 신경세포 이주 및 조직화 장애에서 보이는 간질 증상은 난치성인 경우가 많으나 간질 수술 요법의 발전으로 이 질환의 진단과 치료에 관심이 집중되고 있다. 최근 뇌자기 공명영상(MRI) 도입 이후에 이 질환에 대한 진단이 용이해 지면서 이에 대한 연구가 증가되고 있으니 국내에서는 아직 이 질환에 대한 연구가 미진한 실정이다. 이에 저자들은 신경세포 이주 및 조직화에 장애로 진단된 30례를 대상으로 이 질환의 임상상과 신경 방사선학적 소견을 알아보기 위하여 본 연구를 시행하였다. 방법 : 1989년 9월부터 1995년 8월까지 만 6년동안 서울중앙병원에서 내원하여 뇌자기 공명영상이나 뇌전산화 단층촬영을 시행한 소아환자중에서 신경세포 이주 및 조직화 장애로 진단되었던 30례를 대상으로 방사선학적 소견, 임상증상및 뇌파를 분석하였다. 결과 : 전체 30례중 이소성 회백질이 11례(36.6%)로 가장 많았고, 편평뇌증이 9례(30%) 분열뇌증 6례(20%)의 순이었고 이소성 회백질, 거대뇌증도 각각 2례(6.7%)씩 있었다. 방사선학적 소견은 병소의 위치 및 침범엽의 분포상 편평뇌증, 이송성 희백질은 모두 양측성, 거대뇌증은 모두 일측성이었고 편평뇌증의 경우 중 무뇌-경뇌증에서 무뇌는 모두 두정-후두엽에 있었다. 주된 병변이외의 동반 이상소견증 뇌실 확장이 가장 많았고(14/31, 45.2%), 정체의 16%에서는 다른 형태의 신경세포 이주 및 조직화 장애의 병변이 공존하였다. 임상소견은 간질발작, 운동발달지여느 지능장애 등의 순이었고, 간질발작의 형태는 편평뇌증, 이소성 회백질은 모두 전신 발작이었고 피질 이형성증과 분열뇌증은 부분 발작이 각각 62.5%, 50.0%였다. 뇌파소견상 피질이형성 8례중 7럐(87.5%)에서 초점성 극파 또는 예파 소견이 있었고, 편평뇌증 7례중 3례(42.9%)에서 hypsarrhythmia가 나타났다. 항경련제 투여후 반응은 편평뇌증은 100%(5/5), 피질 이형성증은 66.7%(4/6)에서 1년에 한번 이상의 경련발작을 보여 다른 병변보다 좋지 않았다. 결론 : 임상소견중 간질발작은 병소의 크기와 관계가 없었고 운동발달지연은 병소의 크기가 클수록 많았다. 그러나 정확한 결론을 내리기 위해서는 향후 더 많은 환자를 대상으로 한 연구가 필요하다고 생각된다. Background: The disorders of neuronal migration and organization (or Cortical Malformations) are a complex and rather heterogeous group that are characterized by abnormal structure and function of the cerebral cortex. The causes of disorders of neuronal migration and organization may be both genetic and maternal/environmental. A defect in the radial glial fibers bas been proposed to be the underlying mechanism for migrational arrest in many of the neuronal migration disorders. Morphologically, the disorders can be classified with Lissencephaly, Schizencephaly, Cortical dysplasia, Heterotopia, and Megalencephaly. The clinical and imaging manifestations of these disorders vary considerably. Clinical features include mental retardation of variable of variable degree, neurological signs, and epilepsy. Methods : In this study, we reviewed 30 cases of the disorders of neuronal migration and organization and analyzed their characteristic radiologic, clinical, and EEG findings. Results : The 30patients with neuronal migration and organization disorders consisted of 11 with cortical dysplasia, 9 with lissencephaly, 6 with schizencephaly, 2 with heterotopia, and 2 with megalencephaly. The age of patient at diagnosis ranged from 1days to 15 years of age and mean age was 3.6 years. Associated cerebral anomalies included ventricular dilatation in 14 patients, agenesis of septum pellucidum, and hypoplasis of corpus callosum in 6patients. In addition, among neuronal migration and organization disorders, other types of cortical malformations are mixed in 5patients. Clinically, these patients presented with seizures in 73.3%, motor developmental delay in 50.0%, intellectual retardation in 36.7%, and hypotonia in 3.3%. Patients with large or medium size of neuronal migration disorders had significantly more severe developmental delay than those with small size(P<0.05), but don't have significant difference with regard ti seizure. Conclusion: patients with disorders of neuronal migration and organization can be diagnosed with improved brain imaging techniques. Seizures were the most common clinical manifestation among neurologic manifestations, and patients with larger size of cortical malformations have more motor developmental delay.

신경세포 이주장애 환아의 임상소견과 뇌자기공명 영상 소견과의 상관관계

오광수(Kwang-Soo Oh),최시성(See-Sung Choi) 대한소아신경학회 1998 대한소아신경학회지 Vol.5 No.2

목적 : 신경세포 이주장애는 태생 2-5개월에 뇌실주의 신경세포가 피질쪽으로 이주하여 신경세포층을 형성하는 과정의 이상으로 생기는 선천성발달이상으로 결함의 형태학적 특징에 따라 피질이형성증, 편평뇌증, 분열뇌증, 이소성회백질, 거대뇌증 등으로 분류한다. 최근 MRI의 도입으로 이의 진단이 보다 용이하고 난치성 간질의 한 원인으로 많은 연구가 되고 있다. 본 연구자들은 신경세포 이주장애로 진단된 환아의 임상적 소견을 분석하고 MRI 소견과의 상관관계를 알아보고자 본 연구를 시행하였다. 대상 및 방법 : 1992년 2월부터 1997년 7월까지만 5년 5개월 동안 원광대학병원 소아과에 내원하여 뇌자기공명 영상 촬영을 시행한 환아중에서 신경세포 이주장애로 진단되었던 환아 20례를 대상으로 성별 연령별 분포, 임상소견, 뇌파소견, MRI상 병변의 분류 및 병소의 분포를 분석하고, 병소의 분포에 따른 임상증상의 특징과의 상관관계를 연구하였다. 결과 : 1) 총 20례 중 활택뇌증 9례(45%)이 가장 많았고, 피질 이형성증이 7례(35%), 분열뇌증과 이소성회백질이 각각 2례(10%)이었다. 2) 뇌자기공명 영상 소견상 병소의 위치는 양측이 12례(60%)로 일측의 8례(40%)보다 많았으며, 활택뇌증 9례 모두 양측성이었고 피질 이형성증 7례 중 6례에서 일측성이었으며, 분열뇌증과 이소성회백질은 각각 1례씩 일측성과 양측성 이상 소견을 보였다. 3) 동반된 이상소견은 20례 중 18례에서 출현하였으며 투명중격의 무발생이 4례(20%)로 가장 많았고, 신경세포 이주장애의 분류상 2가지 병변이 공존한 경우가 3례에서 있었다. 4) 임상증상은 경련이 17례(85%)로 가장 많았고, 발육장애 10례(50%), 언어지연 5례(25%), 운동장애 3례(15%), 그리고 주의력결핍 및 과잉행동증후군이 1례 있었다. 5) 신경세포 이주장애 환아의 경련의 형태는 정신경련이 12례(60%), 국소 경련이 5례(25%), 혼합된 경련이 2례(10%)에서 나타났다. 6) 뇌파소견은 16례에서 시행하여 이상소견은 11례(68.7)었으며, 초점성 극파 또는 예파가 3례(18.8%), 전반적인 극파 또는 예파가 1례(6,2%)에서 관찰되었고, 초점성 서파는 1례(6.2%), 전반적인 서파 3례(31.5%), 전반적인 극파 및 서파의 혼합이 2례(12.5%)에서 관찰되었다. 7) 침범된 병소의 범위와 임상증상간의 관계는 양측성의 병변이 있는 환아에서 발육장애가, 일측성의 병변이 있는 환아에서 발육장애가, 일측성의 병소를 가지고 있는 환아에서 운동장애의 빈도가 통계적으로 유의하게 높았다.(p=0.0007, p=0.04) 결론 : 신경세포 이주장애 환아의 주된 증상은 경련이 가장 많았고, 발육장애, 언어지연 및 운동장애의 순이었다. 뇌자기공명 영상 소견상 침범된 병변범위가 양측성인 경우에 발육장애와 일측성인 경우에 운동장애의 출현빈도가 통계적으로 유의하게 높았다. Beginning in the eighth week of fetal life the neuroblasts migrate from the midline to the periphery to form the gray matter of the cerebral cortex. Abnormalities of cell migration are characterized by ectopic location of neurons in the cerebral cortex. This broad group of anomalies include lissencephaly, schizencephaly, cortical dysplasia, gray matter heterotopia, and unilateral hemimegalencephaly. The purpose of this study was to correlate clinical data with anatomic data, which was evaluated by brain magnetic resonance imaging characteristics that are most useful in predicting clinical course. Methods : The clinical records, EEG, and MRI findings of 20 patients with neuronal migration disorders were retrospectively reviewed. Results : The 20 patients with neuronal migration disorders consisted of 11 with lissencephaly, 7 with cortical dysplasia, 2 with heterotopia, and 2 with schizencephaly. Clinically, seizure was the most common symptom in 85%, next developmental delay in 50%, and then delayed speech in 25%, motor deficit 15% in order. The main associated brain anomalies included absence of septum pellucidum in 20%, periventricular leukomalacia in 15%, and corpus callosal agenesis in 15% of patients. Bilateral involvement of lesion in MRI was 60%, comparing to unilateral lesion in 40% of the patients. The most common involed lobes was frontoparietal region. An abnormality of EEG examination was showed in 11 cases of patients(68.7%). Patients with diffuse, bilateral lesion in MRI findings of neuronal migration disorders had significantly developmental delay than those with unilateral lesion(p=0.0007). Patients with unilateral lesion had significantly motor deficit than those with bilateral lesion(p=0.04), Conclusion : Seizures were the most common symptoms among neurological manifestations of neuronal migration disorders. Statistically significant correlations of delayed development with bilateral lesion and motor deficit with unilateral lesion were found.

Control of neuronal migratory through rostral migration stream in mice

Woong Sun,Hyun Kim,Younghye Moon 대한해부학회 2010 Anatomy & Cell Biology Vol.43 No.4

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.

Control of neuronal migration through rostral migration stream in mice

선웅,김현,Younghye Moon 대한해부학회 2011 Anatomy & Cell Biology Vol.43 No.4

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.

GABAergic neuronal development in the embryonic mesencephalon of mice

Kim, Mun-Ki,Lee, Si-Joon,Vasudevan, Anju,Won, Chung-Kil The Korean Society of Veterinary Science 2019 大韓獸醫學會誌 Vol.59 No.4

This study presents neurogenesis and neuronal migration patterns of gamma-aminobutyric acid-ergic (GABAergic) neurons during mesencephalic development of mouse. After neurons from embryonic day (E) 10-16 were labelled by a single injection of 5-bromo-2'-deoxyuridine (BrdU), immunohistochemistry was performed. Neurogenesis were mainly generated in the mesencephalic region at E10 to E13. After E14, BrdU positive cells were observed only in the dorsal mesencephalon. GABAergic neurons were mainly originated in the ventrolateral region of the mesencephalon at the early embryonic stage, especially at E11 to E13. E10-labeled cells showed positive for GABAergic neuron in the basal plate of the mesencephalon at E13. At E15, GABAergic neurons were observed in the entire basal plate and some regions of the ventral and dorsal mesencephalon. They were present in the whole basal plate, the ventral and dorsal mesencephalon of E17, spreading more outward of the mesencephalon at P0. Our study demonstrates that major neurogenesis of GABAergic neurons occurs at E11 to E13. However, neuronal migration continues until neonatal period during mesencephalic development.