Fate Determination of Interneruons in the Mammalian Telecephalon

简介（由申请人提供）：安德森博士是一名医学科学家，他的职业重点是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业知识。研究事业奖励机制下的持续薪酬支持对他的职业发展至关重要。大脑皮层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。基于化学、生理和形态学标准，抑制性中间神经元出现在不同的亚型中，服务于不同的功能。包括癫痫和精神分裂症在内的一些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。最近的研究已经确定，大多数皮层中间神经元来源于基底神经节的腹侧前脑。本研究的长期目标是了解皮层中间神经元亚型分化的分子基础。目的1：区域和时间对中间神经元亚型规范的影响。将采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，来自小鼠端脑皮层和皮层下不同区域的细胞，在皮层神经发生的不同年龄范围内，将在体内和体外移植到新生儿皮层环境中。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，在转录因子Nkx2.1的控制下，生成表达Cre-recombinase的转基因小鼠。这只小鼠将允许对起源于皮层下端脑、内侧神经节隆起和视前区一个亚区域的细胞进行命运定位。目的2和3:Sonic Hedgehog基因在中间神经元亚型分化中的作用。由于有证据表明，中间神经元亚型规范的重要方面发生在前脑腹侧，因此正在采取一种候选分子方法来研究可能影响这一过程的因素。研究的主要因素是Sonic Hedgehog (Shh)，这是一种糖蛋白，参与脊髓腹侧细胞命运的决定，也在前脑腹侧表达。Shh在神经元间规范中的作用将通过体外获得和丧失功能操作进行研究，随后在体内和体外将神经元祖细胞移植到皮层环境中。此外，将使用针对腹侧前脑内Shh表达的条件敲除来研究Shh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.