Neurons in the subcallosal sling

胼胝体下吊带中的神经元

• 批准号: 6747687
• 负责人: Linda J Richards
• 金额: $ 28.22万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6747687
• 关键词: axon; brain septal area; cell differentiation; cell migration; cerebral cortex; confocal scanning microscopy; developmental neurobiology; green fluorescent proteins; laboratory mouse; neuronal guidance; neurons; tight junctions; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): The glial sling was first described by Silver and colleagues in the early 1980's as a population of glioblast cells that arise in the medial aspect of the lateral ventricles. These cells migrate toward the midline during embryogenesis and form tight junctions, creating a sling-like structure that spans the two cerebral hemispheres. When the sling is severed the corpus callosum does not form; in congenitally acallosal mice or in marsupials (which lack a corpus callosum), there is no sling. These observations led to the hypothesis that the sling is required for the corpus callosum to form by guiding callosal axons across the midline. Surprisingly, we have recently discovered that the majority of glial sling cells label with neuronal rather than glial markers (see preliminary data). Preliminary electrophysiological experiments indicate that sling cells have excitable membranes and fire action potentials in response to long depolarizing pulses via whole-cell current clamp. Sling cells from postnatal animals display spontaneous action potentials that are reversibly blocked by TTX. Taken together, these new findings indicate that sling cells are neurons, not glia.Previous descriptive studies found that sling cells migrate from the medial subventricular zone to the midline between E15 and E17 in mice and that the sling disappears early postnatally. Once the sling cells reach the midline, it was proposed that they die and form a small cavity called the cavum septum pellucidum. However 11JNEL labeling shows that only a few cells undergo cell death at E17 and E18. Since the sling continues to be generated until P2 (see preliminary data) the absence of the sling by P5 may be due to additional (or other) mechanisms than cell death, such as cell migration away from the sling area. Preliminary experiments in organotypic slices and adenoviral labeling in vivo suggest that sling cells continue migrating past the midline to other areas of the brain. In aim 1 we extend these findings to determine where sling cells migrate in the developing brain. The sling is continuous with the SVZ of the cortex and may represent a previously unknown population of tangentially or contralaterally migrating cortical neurons. In aim 2 we investigate whether sling cells arise only at the cortico-septal boundary from a specialized sling progenitor population, or whether their progenitors are dispersed in more lateral regions of the SVZ. Using a recombinant retroviral library we determine whether sling cells are clonally related to cells of the cortical plate. Prenatally sling neurons are immature, in aim 3 we investigate their differentiation potential and determine if they are committed to a single, or to multiple, neuronal lineages. These experiments redefine the cellular makeup, migration and possible function(s) of the subcallosal sling during cortical development. Development of the sling is disrupted in a number of genetic acallosal mutants that display additional brain abnormalities. Neurons within the sling may function in the development of the brain and defects in their development may underlie some of these disorders

描述（由申请人提供）：胶质悬带首先由银及其同事在20世纪80年代早期描述为出现在侧脑室内侧的成胶质细胞群。这些细胞在胚胎发育过程中向中线迁移，形成紧密连接，形成跨越两个大脑半球的吊索状结构。当悬带被切断时，胼胝体不会形成;在先天性无胼胝体的小鼠或有袋动物（缺乏胼胝体）中，没有悬带。这些观察结果导致了这样的假设，即吊索是通过引导胼胝体轴突穿过中线形成胼胝体所必需的。令人惊讶的是，我们最近发现，大多数神经胶质吊索细胞的标记与神经元，而不是神经胶质标记（见初步数据）。初步的电生理实验表明，吊索细胞具有可兴奋的膜和火的动作电位响应于长的去极化脉冲通过全细胞电流钳。来自出生后动物的吊索细胞显示被TTX可逆地阻断的自发动作电位。综上所述，这些新发现表明，吊索细胞是神经元，而不是神经胶质细胞。以前的描述性研究发现，吊索细胞从内侧脑室下区迁移到中线之间的E15和E17小鼠和吊索消失出生后早期。一旦悬带细胞到达中线，它们就会死亡并形成一个称为透明隔腔的小腔。然而，11 JNEL标记显示在E17和E18只有少数细胞经历细胞死亡。由于悬带持续产生直至P2（见初步数据），P5时悬带的缺失可能是由于细胞死亡以外的其他（或其他）机制，如细胞迁移离开悬带区域。在器官型切片和腺病毒标记的体内初步实验表明，吊索细胞继续迁移过去的中线到大脑的其他区域。在aim 1中，我们扩展了这些发现，以确定吊索细胞在发育中的大脑中迁移的位置。吊索是连续的SVZ的皮质，并可能代表一个以前未知的人口切线或对侧迁移的皮质神经元。在目标2中，我们调查是否吊索细胞只出现在皮质隔边界从一个专门的吊索祖细胞群体，或是否他们的祖细胞分散在更横向的区域的SVZ。使用重组逆转录病毒库，我们确定是否吊索细胞克隆相关的细胞的皮质板。出生前吊索神经元是不成熟的，在目标3中，我们研究它们的分化潜力，并确定它们是否致力于单一或多个神经元谱系。这些实验重新定义了皮质发育过程中胼胝体下悬带的细胞组成、迁移和可能的功能。吊索的发育在一些遗传性无胼胝体突变体中被破坏，这些突变体显示出额外的大脑异常。吊索内的神经元可能在大脑发育中起作用，其发育缺陷可能是这些疾病的基础