The role of Shox2 in thalamic development and function

丘脑是一个对感觉、运动和认知过程至关重要的大脑区域，因为它位于中央。 在大脑内，与皮质和皮质下区域广泛连接。丘脑功能异常牵涉到 病理情况，如癫痫、自闭症和精神分裂症，但丘脑的特定机制 人们对中断现象知之甚少。丘脑被高度组织成发送输出和接受输入的核团。 从特定的皮质区域。丘脑的神经元携带振荡活动，这对睡眠和 意识状态。这些神经元表达离子通道并接收突触输入，这些突触输入对这些产生缓慢同步振荡的特征放电模式非常重要。了解为调节这些节律的通道的表达奠定基础的机制，以及在发育性心理健康障碍中可能受到异常调节的机制，对于最终预防和开发针对这些疾病的治疗干预措施非常重要。转录因子Shox2代表了一种可能的机制来控制几个对振荡活性重要的离子通道基因的表达。矮个子同源异型盒基因(HSHOX)是一种同源异型盒基因，是肢体发育所必需的重要因子。Shox位于X和Y染色体远端的端粒假常染色体区域1上。Shox单倍体功能不全会导致L-威尔氏软骨发育不良症和特纳综合征，从而导致肢体缩短和畸形。小鼠的同源基因mShox2与Shox基因密切相关，在四肢近端、腭部、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Shox2在中枢神经系统中的表达水平很高，但它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，Shox2在间脑，特别是丘脑背侧核中高度表达，并且Shox2的表达在成熟丘脑中发挥作用，抑制药物诱导的癫痫发作。此外，Shox2对于几个通道亚基的mRNAs的表达是重要的，这些通道亚基对振荡活动是重要的。了解Shox2在大脑发育中的作用对于确定发育障碍的潜在机制是至关重要的。该项目的中心假设是Shox2是一种重要的转录因子，控制着丘脑中继神经元的功能。我们将利用先进的转基因小鼠模型，结合多水平的分析，包括行为、遗传分子和电生理研究，以确定：1)Shox2表达在癫痫发作强度中的作用；2)Shox2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，并将为未来研究可能的机制和基因靶点奠定基础 发育障碍。

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.