Notch Functions in the Adult Nervous System

描述（由申请人提供）：Notch信号在发育细胞命运决定、干细胞增殖调节和许多疾病中发挥着很好的作用。然而，Notch信号对成年神经元的功能也至关重要。Notch在小鼠和果蝇的记忆保持中起作用，但Notch信号在神经元中的作用靶点尚不清楚。我们已经证明秀丽隐杆线虫的lin-12 Notch受体在成年动物中起调节行为的作用。在这里提出的研究中，我们将利用秀丽隐杆线虫中强大的遗传技术，确定Notch信号改变神经元功能和行为的分子途径。在初步筛选中，我们确定了5个在神经系统中表达的基因，它们可能是Notch的直接靶点。这五个基因编码的蛋白质可能对脊椎动物神经元中的Notch信号传导也很重要。在本提案中，我们解决了这些Notch靶基因在成人神经系统中调节神经元活动和行为的机制和途径。

DESCRIPTION (provided by applicant): Notch signaling plays well described roles in developmental cell fate decisions, in the regulation of stem cell proliferation and in numerous diseases. However, Notch signaling is also critical for the function of adult neurons. Notch plays a role in memory retention in mice and Drosophila, yet the targets of Notch signaling in neurons are unclear. We have demonstrated that the C. elegans lin-12 Notch receptor acts in adult animals to modulate behavior. In the studies proposed here, we will identify the molecular pathways by which Notch signaling alters neuronal function and behavior using the powerful genetic techniques available in C. elegans. In a pilot screen, we identified five genes expressed in the nervous system that are likely direct targets of Notch. All five genes encode proteins that are likely critical for Notch signaling in vertebrate neurons as well. In this proposal, we address the mechanisms and pathways by which these Notch target genes act in the adult nervous system to regulate neuronal activity and behavior. PUBLIC HEALTH RELEVANCE: Notch signaling is critical for normal function of the human nervous system. Mutations in Notch3 and Jagged1 cause CADASIL and Alagille syndromes, respectively. These are dominantly inherited disorders associated with stroke and dementia. Combined, their incidence is at least 1 in 50,000, although CADASIL is likely under-diagnosed. Recent evidence also suggests that Notch signaling is up-regulated in Down's syndrome patients. Interestingly, Notch and amyloid precursor proteins directly interact suggesting that Notch signaling may be important in the memory defects associated with Alzheimer's disease. There is no effective treatment for these disorders. Given the conservation across species of Notch regulatory mechanisms and targets, we anticipate that identifying the targets of Notch signaling in C. elegans will reveal critical targets of Notch modulation in humans that are relevant in both normal and pathological conditions.