Establishment of segmental identity in embryonic stem cell derived motor neurons

描述（由申请人提供）：运动功能取决于发育中的神经管中数百种不同的运动神经元（MN）亚型的规格。运动神经元亚型身份是由前后向（AP）模式信号决定的，该信号将原本均匀的神经管细分为分子和功能不同的部分。与对背腹侧模式和一般MN身份的详细了解相比，对脊髓前后侧模式和MN亚型身份获得的分子机制知之甚少。在这里，我们利用我们的能力，直接分化胚胎干细胞为运动神经元获得不同的亚型身份在体外。我们将使用该系统来研究前后身份获取背后的遗传级联：1)我们将定义调节AP模式的外在信号；2)我们将定义AP身份巩固的时间点，3)我们将定义这一过程背后的分子程序。了解胚胎干细胞分化过程中特定神经元节段和亚型身份的获得过程，将对利用胚胎干细胞研究和治疗神经退行性疾病产生影响。单个运动神经元亚型对变性的不同易感性可能为治疗干预提供新的潜在靶点。此外，我们指导MN亚型识别的能力对于有效实施MN细胞替代疗法至关重要。

DESCRIPTION (provided by applicant): Motor function depends on specification of hundreds of distinct motor neuron (MN) subtypes within the developing neural tube. The motor neuron subtype identity is determined by anteroposterior (AP) patterning signals that subdivide the otherwise uniform neural tube into molecularly and functionally distinct segments. In comparison to the detailed understanding of dorsoventral patterning and specification of the generic MN identity, relatively little is known about the molecular mechanisms underlying anteroposterior patterning of the spinal cord and acquisition of MN subtype identity. Here we take advantage of our ability to direct differentiation of ES cells into motor neurons acquiring distinct subtype identities in vitro. We will use this system to study the genetic cascade underlying the acquisition of anteroposterior identity: 1) we will define extrinsic signals that regulate AP patterning; 2) we will define the time point during which AP identity is consolidated and 3) we will define molecular programs that underlie this process. Gaining insight into the process of acquisition of specific neuronal segmental and subtype identities during ES cell differentiation will have an impact on the utilization of ES cells to study and treat neurodegenerative diseases. The differential susceptibility of individual motor neuron subtypes to degeneration might reveal new potential targets for therapeutic intervention. In addition, our ability to direct MN subtype identity will be essential for effective implementation of MN cell replacement therapies.