The role of Shox2 in thalamic development and function

Shox2 在丘脑发育和功能中的作用

• 批准号: 9344710
• 负责人: Laura Schrader
• 金额: $ 18.81万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9344710
• 关键词: Adult; Age; Animals; Area; Autistic Disorder; Behavior; Behavioral Genetics; Brain; Cardiac Myocytes; Cell Nucleus; Cells; Characteristics; Cognitive; Conscious; Data; Development; Disease; Distal; Dorsal; Electrophysiology (science); Epilepsy; Foundations; Future; Gene Expression; Generations; Genes; Genetic; Heart; Homeobox; Homeobox Genes; Homologous Gene; Individual; Interneurons; Ion Channel; Knock-out; Lead; Leri-weill dyschondrosteosis; Limb Development; Limb structure; Mediating; Mental disorders; Molecular Genetics; Motor; Mus; Nervous system structure; Neuraxis; Neurodevelopmental Disorder; Neurons; Output; Pacemakers; Palate; Pathologic; Pattern; Pharmacology; Play; Property; Pseudoautosomal Region; Regulation; Role; Schizophrenia; Seizures; Sensory; Severities; Sleep; Slow-Wave Sleep; Spinal Cord; Spinal Ganglia; Synapses; Thalamic structure; Therapeutic Intervention; Transgenic Mice; Turner' s Syndrome; Unconscious State; X Chromosome; Y Chromosome; developmental disease; diencephalon; emerging adult; experimental study; hyperpolarization-activated cation channel; mRNA Expression; mouse model; multilevel analysis; mutant; nervous system development; overexpression; postnatal; prevent; protein expression; recombinase-mediated cassette exchange; transcription factor

The thalamus is a brain area that is critical for sensory, motor, and cognitive processing as it is located centrally within the brain and connects extensively with cortical and subcortical areas. Aberrant thalamic function is implicated in pathological conditions such as epilepsy, autism, and schizophrenia, but the specific mechanisms of the thalamic disruptions are poorly understood. The thalamus is highly organized into nuclei that send outputs to and receive inputs from specific cortical areas. The neurons of the thalamus entrain oscillatory activity that is important for sleep and conscious state. These neurons express ion channels and receive synaptic inputs that are important for these characteristic firing patterns that generate slow synchronized oscillations. Understanding the mechanisms that lay the foundations for expression of the channels that mediate these rhythms and can be aberrantly regulated in developmental mental health disorders is important to ultimately prevent and develop therapeutic interventions for these disorders. The transcription factor, Shox2, represents a possible mechanism to control expression of several ion channel genes important for oscillatory activity. The short stature homeobox-containing gene (hSHOX) is a homeobox gene that is an important factor that is required for limb development. SHOX is present on the telomeric pseudoautosomal region 1 at the distal end of the X and Y chromosomes. SHOX haploinsufficiency causes Léri-Weill dyschondrosteosis and Turner Syndrome, which result shortened and malformed limbs. The mouse homologue, mShox2, is closely related to the SHOX gene and plays a role in the development of proximal limbs, palate, heart, dorsal root ganglia neurons, and interneurons of the spinal cord. Despite high levels of expression in the central nervous system, the role of Shox2 in the development of the nervous system is essentially unknown. Our preliminary data suggest that Shox2 is highly expressed in the diencephalon, particularly nuclei within the dorsal thalamus, and that Shox2 expression plays a functional role in the mature thalamus, suppressing pharmacologically-induced seizures. Furthermore, Shox2 is important for expression of mRNAs for several channel subunits that are important for oscillatory activity. Understanding the role of Shox2 in brain development is imperative to determine mechanisms underlying developmental disorders. The central hypothesis of this project is that Shox2 is an important transcription factor that controls the function of thalamic relay neurons. We will take advantage of cutting-edge transgenic mouse models and combine multi-level analysis, including behavior, genetic molecular, and electrophysiological studies to determine: 1) the role of Shox2 expression in seizure intensity and 2) the role of Shox2 in oscillatory behavior of thalamic neurons. These aims will enhance our understanding of thalamic development and will lay the groundwork for future studies investigating possible mechanisms and genetic targets that are dysregulated in developmental disorders.

丘脑是大脑的一个区域，因为它位于中枢，所以对感觉、运动和认知处理至关重要。 在大脑内，并广泛连接皮层和皮层下区域。异常的丘脑功能与 病理条件，如癫痫，自闭症和精神分裂症，但丘脑的具体机制， 人们对干扰的认识很不清楚。丘脑是高度组织成核，发送输出和接收输入 特定的皮层区域。丘脑的神经元产生对睡眠很重要的振荡活动， 意识状态。这些神经元表达离子通道并接收突触输入，这些突触输入对于产生缓慢同步振荡的特征性放电模式是重要的。了解为表达调节这些节律的通道奠定基础的机制，并在发育性精神健康障碍中进行异常调节，对于最终预防和开发这些疾病的治疗干预措施非常重要。转录因子Shox 2代表了控制对振荡活性重要的几种离子通道基因表达的可能机制。含矮身材同源框基因（hSHOX）是一种同源框基因，是肢体发育所需的重要因素。SHOX存在于X和Y染色体远端的端粒假常染色体区域1上。SHOX单倍不足导致Léri-Weill软骨发育不良和Turner综合征，导致肢体缩短和畸形。小鼠同源物mShox 2与SHOX基因密切相关，在近端肢体、腭、心脏、背根神经节神经元和脊髓中间神经元的发育中发挥作用。尽管Shox 2在中枢神经系统中有高水平的表达，但其在神经系统发育中的作用基本上是未知的。我们的初步数据表明，Shox 2是高度表达的间脑，特别是背侧丘脑内的核，Shox 2的表达在成熟的丘脑中发挥功能性作用，抑制药理学诱导的癫痫发作。此外，Shox 2对几个通道亚基的mRNA表达很重要，这些亚基对振荡活性很重要。了解Shox 2在大脑发育中的作用对于确定发育障碍的潜在机制至关重要。该项目的中心假设是Shox 2是控制丘脑中继神经元功能的重要转录因子。我们将利用最先进的转基因小鼠模型和联合收割机多层次的分析，包括行为，遗传分子和电生理研究，以确定：1）Shox 2表达在癫痫发作强度中的作用和2）Shox 2在丘脑神经元振荡行为中的作用。这些目标将增强我们对丘脑发育的理解，并为未来研究丘脑发育异常的可能机制和遗传靶点奠定基础。 发育障碍