Fate Determination of Interneruons in the Mammalian Telecephalon

简介(申请人提供)：安德森博士是一名内科科学家，他的职业生涯专注于大脑皮层发育的分子机制，以及精神分裂症的临床和研究专长。在研究事业奖励机制下继续提供薪金支援，对他的职业发展至为重要。大脑皮质包含两种类型的神经元，兴奋性投射神经元和抑制性中间神经元。根据化学、生理和形态标准，抑制性中间神经元以不同的亚型出现，这些亚型具有不同的功能。包括癫痫和精神分裂症在内的几种常见疾病可能涉及特定中间神经元亚型的异常发育和/或功能障碍。最近的研究确定，大多数皮质中间神经元来自腹侧前脑，位于基底节的原始处。这项研究的长期目标是了解皮质中间神经元亚型规范的分子基础。目标1：区域和时间对中间神经元亚型规范的影响。将使用两种方法来检查不同的中间神经元亚型是否有不同的来源。首先，来自小鼠端脑不同皮质和皮质下区域的细胞，在不同的皮质神经发生年龄范围内，将被移植到体内和体外的新生皮质环境中。将评估供体细胞的出生地点和时间对其分化命运的影响。其次，将产生在转录因子Nkx2.1控制下表达Cre-重组酶的转基因小鼠。这只小鼠将允许绘制起源于皮质下端脑、内侧神经节隆起和视前区的一个分区内的细胞的命运图。目标2和3：Sonic Hedgehog在中间神经元亚型规范中的作用。由于证据表明中间神经元亚型规范的重要方面发生在腹侧前脑，一个候选分子方法正被用来研究可能影响这一过程的因素。正在研究的主要因素是Sonic Hedgehog(Shh)，一种参与决定腹侧脊髓细胞命运的糖蛋白，也在腹侧前脑表达。Shh在中间神经元规范中的作用将通过体外获得和丧失功能的操作，随后将神经前体细胞移植到体内和体外的皮质环境中来研究。此外，将使用针对腹侧前脑内Shh表达的条件性基因敲除来研究Shh的功能。

DESCRIPTION (provided by applicant): Dr. Anderson is a physician-scientist who has a career focus on the molecular mechanisms of cerebral cortex development, as well as clinical and research expertise in schizophrenia. Continued salary support under the Research Career Award mechanism will be crucial to his career development. The cerebral cortex contains two types of neurons, excitatory projection neurons and inhibitory interneurons. Based on chemical, physiological and morphological criteria, the inhibitory interneurons occur in distinct subtypes that subserve distinct functions. Several common illnesses, including epilepsy and schizophrenia may involve the abnormal development and/or dysfunction of particular interneuron subtypes. Recent studies have determined that most cortical interneurons derive from the ventral forebrain, in the anlage of the basal ganglia. The long-term objective of this research is to understand the molecular basis for cortical interneuron subtype specification. Aim 1: Regional and temporal influences on interneuron subtype specification. Two methods will be employed to examine whether distinct interneuron subtypes have distinct sources. First, cells from various cortical and subcortical regions of mouse telencephali, at various times over the age-range of cortical neurogenesis, will be transplanted into neonatal cortical environments in vivo and in vitro. The effect of the donor cell's place and time of birth on their differentiated fate will be assessed. Second, a transgenic mouse expressing Cre-recombinase under control of the transcription factor Nkx2.1 will be generated. This mouse will permit fate-mapping of cells that originated within a subregion of the subcortical telencephalon, the medial ganglionic eminence and preoptic area. Aims 2 and 3: The role of Sonic Hedgehog in interneuron subtype specification. Since evidence suggests that important aspects of interneuron subtype specification occur within the ventral forebrain, a candidate molecule approach is being taken to study factors which may influence this process. The primary factor being examined is Sonic Hedgehog (Shh), a glycoprotein involved in cell fate determination in the ventral spinal cord which is also expressed in the ventral forebrain. Shh's role in interneuron specification will be studied by in vitro gain and loss of function manipulations followed by transplantation of neuronal progenitors into cortical environments in vivo and in vitro. In addition Shh function will be studied using conditional knockouts that target Shh expression within the ventral forebrain.