神经嵴细胞迁移障碍在先天性巨结肠发病中的作用研究进展

神经嵴细胞起源于神经和非神经外胚层的交界处(神经板交界处), 具有显著的多能性和迁移能力, 在胚胎中广泛迁移至最终目的地, 分化成相应组织或器官。先天性巨结肠(Hirschsprung disease, HSCR)是由于胚胎早期神经嵴细胞迁移障碍, 导致胚胎期肠管缺乏足够数量的肠神经嵴细胞定植, 因而导致肠神经系统形成障碍, 而引起患儿腹胀便秘等症状的先天性消化道畸形。因此, HSCR的发病与神经嵴细胞迁移异常密切相关。现就细胞外基质的降解和重构、神经嵴细胞上皮-间质转化以及细胞间突起形成影响神经嵴细胞迁移的研究现状进行综述。     

先天性巨结肠症的病因学研究进展

先天性巨结肠症病因学主要研究进展是遗传因素及胚胎早期微环境改变.遗传因素包括RET-GDNF系统、EDNRB-EDN3系统及其参与调控的基因(SOX10、NRG-1、FoxD3、PHOX2B、HOXB5、ZFHX1B等),为神经嵴细胞迁移和分化所必需.胚胎早期微环境变化包括Cajal质细胞、细胞黏附分子L1、Ca2+等.细胞黏附分子L1可能是神经嵴来源细胞迁移与分化的基础,Ca2+依赖途径的表达减少造成平滑肌收缩活性异常.     

肠神经系统发育的研究进展北大核心CSCD

肠神经系统是由肠神经元和神经胶质细胞组成的网络体,它起源于神经嵴干细胞。而神经嵴干细胞在多种细胞因子及信号分子的参与下,经历增殖、迁移及分化过程,形成各种类型的肠道细胞。这些细胞分别表达不同的神经递质和神经肽,共同调控肠道的功能。胚胎期肠神经系统的发育障碍是先天性巨结肠症(Hirschsprung’s disease,HSCR)的根本原因。近年来,胚胎期肠管神经发育的研究取得了一些进展,尤其是在信号通路及其与HSCR的关系上,这也为HSCR的治疗提供了一些借鉴。     

粘附分子及其配体在先天性巨结肠发生中的作用

先天性巨结肠(HSCR)是一种常见的胃肠道发育畸形,有遗传倾向,其病理基本变化是病变肠段肌间神经丛和粘膜下神经丛内神经节细胞完全缺如。关于神经节细胞缺如的原因目前主要有以下三种学说:①胚胎发育期,形成神经元的神经嵴细胞分化及向肠道移行过程中发生障碍,停顿越早无神经节细胞段越长;②神经嵴细胞迁移到肠壁中去后某些局部因素的变化,如肠道缺血的作用,阻止了峭细胞聚集或导致已聚集起来的细胞     

RA—BMPs信号通道对肠神经系统发育调控的研究进展

肠道神经系统是起源于神经嵴的神经元前体细胞迁移至肠道并演化形成,而起源于神经嵴的前体细胞是多潜能干细胞,它们在肠道内所接触的微环境决定了肠道神经系统的独特性。神经营养因子如胶质细胞源性神经生长因子（glial derived neurotrophic factor,GDNF）、营养以及细胞外基质成分在肠道神经元前体细胞迁移增殖分化中起重要作用。     

先天性巨结肠症的病因学研究进展

先天性巨结肠症病因学主要研究进展是遗传因素及胚胎早期微环境改变.遗传因素包括RET-GDNF系统、EDNRB-EDN3系统及其参与调控的基因(SOX10、NRG-1、FoxD3、PHOX2B、HOXB5、ZFHX1B等),为神经嵴细胞迁移和分化所必需.胚胎早期微环境变化包括Cajal质细胞、细胞黏附分子L1、Ca2+等...     

先天性巨结肠DNA甲基化的研究进展

先天性巨结肠(Hirschsprung's disease,HSCR)是一种多基因与环境共同作用的复杂疾病,遗传易感性和胚胎期肠道微环境紊乱是其发病的两大主要原因,但其病因及发病机制仍不明确。随着对HSCR发病机制不断深入的研究,发现DNA甲基化异常可能参与神经嵴细胞的增殖、成熟、分化和迁移等过程,从而导致HSCR发生。     

先天性巨结肠症分子基因学研究进展

先天性巨结肠症是由多种因素导致胚胎期肠神经嵴细胞发育异常而引起的一种小儿外科常见病,多个基因或基因信号通路参与其病理发生过程。迄今为止,人们发现了至少11个与先天性巨结肠症发生相关的易患基因,这些基因的表达异常或相互作用异常可导致神经嵴细胞发育异常,引起先天性巨结肠症。该文就易患基因及其在先天性巨结肠症发生中的作用进行综述。     

神经嵴细胞与先天性心脏病发病机制

先天性心脏病的发病机制十分复杂,近年来的研究显示,心脏神经嵴细胞与胚胎时期心脏锥干部发育密切相关.一些影响心脏神经嵴发育的相关基因也已经被发现,这些基因通过影响心脏神经嵴细胞的分化及迁移而导致心室肌细胞及心室流出道结构的发育异常.因此,了解这些基因的功能有助于进一步揭示锥干部畸形的先天性心脏病的发病机制.     

神经嵴细胞与先天性心脏病发病机制

先天性心脏病的发病机制十分复杂,近年来的研究显示,心脏神经嵴细胞与胚胎时期心脏锥干部发育密切相关.一些影响心脏神经嵴发育的相关基因也已经被发现,这些基因通过影响心脏神经嵴细胞的分化及迁移而导致心室肌细胞及心室流出道结构的发育异常.因此,了解这些基因的功能有助于进一步揭示锥干部畸形的先天性心脏病的发病机制.     

The influence of the stage of differentiation of the gut on the migration of neural cells: an experimental study of Hirschsprung's disease

Based on experimental studies in mutant mouse strains, an imbalance between the rate of migration of neural crest cells and the rate of differentiation of the mesenchyme of the distal gut has been proposed as an etiological factor in Hirschsprung's disease. We studied the influence of the stage of differentiation of embryonal chick gut on the migration of neural crest cells in an in vivo culture system: the chorioallantoic membrane. Neural crest cells in cultured gut were demonstrated with antibodies directed against the HNK-1 epitope. Enteric neurons were demonstrated with neurofilament immunoreactivity. By culturing isolated gut segments of E4 embryos, we obtained aneuronal (neurofilament-negative) embryonal chick gut up to 25 days of development. In cocultures of aneuronal gut and the neural anlage (neural tube and neural crest) neural crest cell colonization was observed, even in advanced stages of differentiation. The significance of the results is discussed in terms of the etiology of Hirschsprung's disease.     

Cardiac morphogenesis--recent research advances

It has been demonstrated recently that a specific region of neural crest contributes cells to the septa of the outflow tract of the heart. Removal of this region of cardiac neural crest prior to migration from the neural fold results in persistent truncus arteriosus in chick embryos. Removal of other regions of cranial neural crest results in double outlet right ventricle. Since double outlet right ventricle is produced by manipulation of noncardiac neural crest, this malformation is thought to be an indirect rather than direct effect of neural crest ablation. The cranial neural crest forms the walls of all of the aortic arch arteries and it is proposed herein that flow abnormalities are produced in the pharyngeal region by injury to the neural crest. These abnormal hemodynamic characteristics influence heart development. Cardiac neural crest seeds the heart with parasympathetic postganglionic neurons as well as ectomesenchyme. Removal of the cardiac neural crest results in cardiac malformations because of the decreased ectomesenchymal cells. However, the neural population undergoes regeneration and so the innervation of malformed hearts is morphologically normal. The mechanism for this regeneration is not understood.     

Goldenhar syndrome and neuroblastoma: a chance association?

Oculoauriculovertebral dysplasia, also called Goldenhar syndrome, includes several anomalies: epibulbar dermoids or lipodermoids, microtia, mandibular hypoplasia, vertebral, skeletal, cardiac and kidney anomalies, among others. Tumours have also been observed in patients with oculoauriculovertebral dysplasia. We report the first case of oculoauriculovertebral dysplasia associated with a neuroblastoma. This tumour consists of cells identical to early migratory neural crest cells in the embryo. Several theories have been proposed regarding the pathogenetic explanation of oculoauriculovertebral dysplasia. Currently, some researchers have suggested a deficiency in mesodermal formation or defective interaction between neural crest and mesoderm as a possible aetiology. CONCLUSION: It is suggested that the case reported here is an additional argument for an anomaly in neural crest cell migration or interaction with the mesoderm in the pathogenesis of oculoauriculovertebral dysplasia.     

Pathogenesis of a Bisdiamine-Induced Malformation Complex in Rat Resembling DiGeorge Syndrome

Abstract Administration of the antispermatogenic agent bis-diamine (N, N'-bis-(dichloroacetyl)-1, 8-octamethylenediamine) to pregnant rats produced a malformation complex resembling DiGeorge syndrome in man. The malformations consisted of hypoplasia or aplasia of the thymus, persistent truncus arteriosus, tetralogy of Fallot, aberrant subclavian artery and other cardiovascular anomalies, as well as hypoplasia of the parathyroid gland, thyroid gland, and the spleen. The malformation complex appeared with a high incidence when the drug was administered on day 9.5 or day 10 of gestation.
Since the connective tissues of the thymus, aorticopulmonary septum, smooth muscles of the media of the aortic arch artery, and connective tissues of the parathyroid and the thyroid glands, are of neural crest origin, and since the time of their migration is around day 10 of gestation, we postulate that the action of bis-diamine might be involution of the migration of the neural crest cells and of its pathways.
We further suggest from the findings of persistent atrioventricular canal and hypoplasia of the spleen, that the drug must have also affected the growth of mesenchymal cells, which originate from the endocardial epithelial cells.     

Familial interruption of the aortic arch

Summary Interruption of the aortic arch (IAA) is an important congenital cardiac malformation occurring in 1.4% of cases with a congenital cardiac malformation. Only two reports have described IAA in siblings, each with type B and an anomalous right subclavian artery. We report the occurrence of IAA type B with an anomalous right subclavian artery in two siblings and their half-sibling, each of whom had additional conotruncal cardiac malformations. Recent evidence suggests that conotruncal cardiac malformations, including IAA type B, are related to abnormalities of neural crest cell migration. Thus, the family reported herein may manifest a syndrome related to alterations in mesenchymal tissue/neural crest cell migration.     

The extracellular matrix and its role in cell migration and development of the enteric nervous system.

The extracellular matrix (ECM), a network consisting of many different macromolecules, fulfils many important functions in every multicellular organism, especially during their development. Among other factors, ECM molecules are necessary for cell migration and also regulate cell differentiation, as could be shown in a wide range of animals. The enteric nervous system (ENS) is built up by neural crest cells (NCC) migrating along predetermined pathways into the developing gut. Studies done for example in mice and chickens did not only enable scientists to reconstruct these routes but also to demonstrate their dependence on ECM molecules such as laminin. Currently we are investigating the influence of different ECM constituents, growth factors and noxious factors on NCC migration and differentiation in the developing chicken gut. The easy handling of the chicken embryo and the use of different methods will give us valuable insights for further investigations.     

Setleis Bitemporal "Forceps Marks" Syndrome and Its Pathogenesis: A Case Report

Setleis bitemporal "forceps marks" syndrome is characterized by "forceps marks" and a peculiar facies. The syndrome has previously been reported mainly in the Puerto Rican population. We describe here a Japanese boy with the syndrome. In addition, the hypothesis is presented that the Setleis syndrome may result from an insufficient migration of neural crest cells into the frontonasal process and the first branchial arch.     

Teratogenic effect of bis-diamine on embryonic rat heart

ABSTRACT  Bis-diamine induces conotruncal anomalies including persistent truncus arteriosus, tetralogy of Fallot, interruption of the aortic arch, and ventricular septal defect in rat embryos when administered to the mother. Bis-diamine also induces extracardiac malformations including thymic hypoplasia, facial dysmorphism, forelimb anomalies and diaphragmatic hernia. However, the teratogenic mechanisms of this chemical in early developing rat hearts have not been fully established. Chimeric studies in chick and quail embryos demonstrated that the cranial neural crest cells reached the cardiac outflow tract, contributing to aorticopulmonary and truncal septation. Since an ablation of the cranial neural crest also produced the conotruncal anomalies, bis-diamine is proposed to disturb the normal migration of cardiac neural crest cells to the heart. Based on our data concerning cardiac anomalies induced by bis-diamine, we reviewed how the cardiac malformations were morphologically established in early developing rat hearts. Our data showed that 1) cardiovascular anomalies induced by bis-diamine are time- and species or strain- dependent. 2) bis-diamine reduces the number of neural crest cells migrating to participate in the conotruncal septation, 3) bis-diamine induces anomalous coronary arteries, thin ventricular walls and epicardial defects, and 4) some embryos cultured in the medium containing bis-diamine had extra-cardiac abnormalities including abnormal location of the otic placodes and delay in mid brain closure. Conclusively, bis-diamine does not appear to merely affect the cardiac development, but rather disturbs normal development of all the organs contributed to by neural crest cells.