Neurons in the subcallosal sling

胼胝体下吊带中的神经元

• 批准号: 6612638
• 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 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6612638
• 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(申请人提供)：胶质吊带首先由Silver及其同事在20世纪80年代初由S描述为一群出现在侧脑室内侧的胶质母细胞。这些细胞在胚胎发育期间向中线迁移，形成紧密的连接，形成横跨两个大脑半球的吊带状结构。当背带被切断时，不会形成胼胝体；在先天性无足小鼠或有袋类动物(没有胼胝体)中，没有背带。这些观察结果导致了一种假说，即通过引导胼胝体轴突穿过中线，必须使用吊带才能形成穹窿体部。令人惊讶的是，我们最近发现，大多数神经胶质细胞标记的是神经元标记，而不是神经胶质标记(见初步数据)。初步的电生理实验表明，吊索细胞通过全细胞电流钳对长的去极化脉冲作出响应，具有可兴奋的膜和放电动作电位。出生后动物的吊索细胞显示出可被TTX可逆地阻断的自发动作电位。综上所述，这些新的发现表明，吊索细胞是神经元，而不是神经胶质。以前的描述性研究发现，吊索细胞在小鼠E15至E17之间从内侧脑室下区迁移到中线，并在出生后早期消失。一旦吊索细胞到达中线，就被认为是死亡，并形成一个称为透明隔腔的小腔。然而，11JNEL标记显示，只有少数细胞在E17和E18发生细胞死亡。由于吊索持续产生到P2(见初步数据)，P5之前吊索的缺失可能是由于除细胞死亡之外的其他(或其他)机制，例如细胞迁移离开吊索区。器官切片和体内腺病毒标记的初步实验表明，吊索细胞继续从中线迁移到大脑的其他区域。在目标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到哪里。吊索与皮质的SVZ是连续的，可能代表了以前未知的切向或对侧迁移的皮质神经元群体。在目标2中，我们研究了吊索细胞是否只出现在皮质-中隔交界处，来自特定的吊带祖细胞群体，或者它们的祖细胞是否分散在SVZ的更外侧的区域。利用重组逆转录病毒文库，我们确定了吊索细胞是否与皮质板细胞克隆相关。产前吊带神经元是不成熟的，在目标3中，我们研究它们的分化潜力，并确定它们是致力于单个神经细胞谱系，还是多个神经细胞谱系。这些实验重新定义了皮质发育过程中穹隆下吊带的细胞组成、迁移和可能的功能(S)。在一些表现出额外大脑异常的遗传非同种异体突变体中，吊带的发育被扰乱。吊索内的神经元可能在大脑的发育过程中发挥作用，它们的发育缺陷可能是其中一些障碍的原因。