Regulation of Glutamate and GABA neuron development

描述(申请人提供)：哺乳动物神经系统由数千种不同的神经细胞类型组成。然而，它们要么是兴奋的，要么是抑制的。主要的兴奋性和抑制性神经递质分别是氨基酸谷氨酸和GABA(伽马氨基丁酸盐)。在开发过程中，这两个发射器是以互斥的方式指定的。这一提议的广泛目标是了解这一非常重要的命运选择决定所依据的分子机制。在初步研究中，我们将重点放在神经系统发育中一个解剖学上定义明确的区域--脊髓背角。我们发现TLX类转录因子在细胞命运选择中具有双重功能：促进谷氨酸和抑制GABA神经元发育。因此，在TLX基因缺失的小鼠中，背角中的谷氨酸能感觉细胞转化为GABA能神经元。我们的研究计划建立在这些初步数据的基础上。我们有三个具体目标。目的1是确定TLX功能在谷氨酸能和GABA能命运选择中的解剖范围。这种TLX功能是局限于脊髓的背角，还是延伸到中枢神经系统的其他TLX阳性区域--特别是后脑的感觉核？解决这个问题将确定谷氨酸和GABA的二元规范是否是神经系统中的共同主题，并可能为TLX基因缺失的小鼠遭受类似人类先天性低通气综合征的呼吸问题提供洞察。目的2是确定TLX蛋白在命运选择过程中的作用。我们的初步研究表明，TLX蛋白是谷氨酸神经元发育所必需的。在这里，我们将使用遗传功能增益来确定TLX蛋白是否足以指定不同脑区的谷氨酸递质表型。此外，我们将确定TLX蛋白是否直接或间接促进谷氨酸能神经元分化。目的3确定TLX蛋白在抑制GABA神经元分化中的结构基础。在人类中枢神经系统中，兴奋和抑制之间的平衡被破坏，这是癫痫、精神分裂症和疼痛障碍等神经疾病的基础。因此，这里描述的研究将对这些疾病的管理具有实际意义。

DESCRIPTION (provided by applicant): The mammalian nervous system is composed of thousands of distinct neuronal cell types. However, all of them are either excitatory or inhibitory. The principal excitatory and inhibitory neurotransmitters are the amino acids glutamate and GABA (gamma-aminobutyrate), respectively. During development, these two transmitters are specified in a mutually exclusive manner. The broad goal of this proposal is to understand the molecular mechanism that underlies this very important fate choice decision. In preliminary studies, we have focused upon an anatomically well-defined region of the developing nervous system - the dorsal horn of the spinal cord. We have found that the Tlx-class transcription factors have a dual function in cell fate choice: promoting glutamate and suppressing GABA neuron development. Thus, in Tlx-null mice, glutamatergic sensory cells in the dorsal horn are transformed into GABAergic neurons. Our study plan builds upon this preliminary data. We have three specific aims. Aim 1 is to define the anatomical range of Tlx function in the glutamatergic versus GABAergic fate choices. Is this Tlx function confined to the dorsal horn of the spinal cord or does it extend to other Tlx-positive regions of the central nervous system - specifically, the sensory nuclei in the hindbrain? Addressing this question will determine whether binary specification of glutamate and GABA is a common theme in the nervous system and may also provide insight into why Tlx-null mice suffer a breathing problem that resembles human congenital hypoventilation syndrome. Aim 2 is to define the roles of Tlx proteins in the fate choice process. Our preliminary studies show that Tlx proteins are necessary for glutamate neuron development. Here we will use genetic gain-of-function to determine whether Tlx proteins are sufficient to specify glutamate transmitter phenotype in various brain areas. In addition, we will determine whether Tlx proteins directly or indirectly promote glutamatergic neuron differentiation. Aim 3 is to define the structural basis of Tlx proteins in suppression of GABA neuron differentiation. Within the human CNS, a disruption of the balance between excitation and inhibition underlies neurological disorders, such as epilepsy, schizophrenia, and pain disorders. Accordingly the studies described here will have practical overtones for the management of these diseases.