Sensory and metabolic regulation of stem cell niche function

食物丰富程度改变发育和繁殖的机制并不是 很好理解。我们发现在C。 这提供了一个前所未有的机会来确定食物环境 在发育过程中促进干细胞库的扩大。具体来说，我们发现， 来自ASI神经元的DAF-7/转化生长因子？信号促进生殖系干细胞的积累 在生殖成熟之前的发育期。这一规定的不同之处在于 根据前面描述的DAF-7/转化生长因子？的基本作用，包括组织- 对转化生长因子β受体和下游基因依赖性的要求。在神经元到- NICE系统中，干细胞NICE中需要转化生长因子？受体来应答 丰富的食物。在那里，转化生长因子受体途径调节基因Lag-2的转录 它编码Notch受体的配体，该受体在附近的生殖系干细胞中表达。 生殖系干细胞中的缺口活性阻止了它们的分化，从而促进了 他们在发展过程中的积累。因此，食物--通过神经元转化生长因子--调节 干细胞生态位中的一种关键因子的表达，使丰富的食物扩大 生殖系干细胞库。我们将利用线虫的工具和功能 (包括明确的解剖学、复杂的遗传学、单细胞分辨率、方便的饮食 操纵和实时成像)，以及在利基中LAG-2表达的定量读数， 以进一步阐明这种神经元到壁龛系统的机制基础。我们会 确定(I)传递信号的神经元的转化生长因子？信号的分子机制 摄食量的差异，(Ii)神经元转化生长因子？ 小生境滞后-2反应，(Iii)神经元感觉活动的作用(与其他 神经调节或代谢输入)(Iv)生态位反应的敏感性和动力学 改变食物丰度，以及(V)微生物环境的成分(感官 和/或营养)，调节依赖于转化生长因子信号的LAG-2的表达。分子 在这个系统中工作的通路是高度保守的，并与干细胞生物学有关 和人类疾病状态，尤其是癌症。因此，该项目将推进基本 科学知识，对包括生育在内的许多普通医学领域有影响， 癌症和再生医学。

The mechanisms by which food abundance modifies development and reproduction are not well understood. We identified a “neuron-to-niche” (TGFß-to-Notch) signaling mechanism in C. elegans that provides an unprecedented opportunity to determine how the food environment promotes the expansion of a stem cell pool during development. Specifically, we found that DAF-7/TGFß signaling from ASI neurons promotes the accumulation of germline stem cells during the period of development just prior to reproductive maturity. This regulation differs in fundamental ways from previously described roles for DAF-7/TGFß, including tissue- requirement for the TGFß receptor and downstream genetic dependencies. In the neuron-to- niche system, the TGFß receptor is required in the stem cell niche for the response to abundant food. There, the TGFß receptor pathway regulates the transcription of lag-2, a gene that encodes a ligand for the Notch receptor that is expressed in nearby germline stem cells. Notch activity in the germline stem cells prevents their differentiation and thereby facilitates their accumulation during development. Therefore, food – via neuronal TGFß – regulates the expression of a critical factor in the stem cell niche such that abundant food expands the germline stem cell pool. We will take advantage of the tools and features of C. elegans (including defined anatomy, sophisticated genetics, single-cell resolution, facile dietary manipulation, and live imaging), and the quantitative readout of lag-2 expression in the niche, to further elucidate the mechanistic underpinnings of this neuron-to-niche system. We will determine (i) the molecular mechanisms of TGFß signaling from the neurons that convey differences in food quantity, (ii) the quantitative relationship between neuronal TGFß and the niche lag-2 response, (iii) the role of sensory activity of the neuron (versus other neuromodulatory or metabolic inputs) (iv) the sensitivity and dynamics of the niche response to altered food abundance, and (v) the components of the microbial environment (sensory and/or nutritive) that regulate TGFß signaling-dependent lag-2 expression. The molecular pathways that work in this system are highly conserved and are implicated in stem cell biology and human disease states, especially cancer. Therefore, the project will advance basic scientific knowledge, with implications for many general medical areas, including fertility, cancer, and regenerative medicine.