果蝇生殖干细胞分化调控网络随机动力学研究

In developmental biology, stem cells interact with surrounding stromal cells (or niche) via signaling pathways to precisely balance stem cell self-renewal and differentiation. However, little is known about how niche signals are transduced dynamically and differentially to stem cells and their intermediate progeny and how the fate switch of stem cell to differentiating cell is initiated. In our experiment research, the gene bam, which determined the fate of the Drosophila ovarian germline stem cells (GSC), is regulated by a complex genetic regulation network composed by Dpp, Tkv, pMad and Fused. Our researches about this genetic regulation network showed that environmental signaling Dpp is essential for GSC switch between mono-stable state and bi-stable states of the system. In this project, we will do the following things: (i) the stationary statistics about the genetic regulation network, i.e., the transition of the expression noises (fluctuations) of each element in the system along the regulation pathway and the connection between the noises and the regulation strength; (ii) the transition rate (or probability) between the two local-stable states if the system is bistable; (iii) diffusion of niche-dependent signaling Dpp and irreversibility of differentiation of the Drosophila ovarian germline stem cells, i.e., both the steep gradient of Dpp activity along with “GSC-preCB-CB” and the feedback loop between Tkv and Fused determine GSC fate and its irreversibility of differentiation.

在发育生物学中,微环境信号如何动态和差异地在干细胞及其分化子细胞中传导并发挥作用，进而导致干细胞的不对称分裂是一个具有重要意义的科学问题。我们的实验研究发现在果蝇生殖干细胞分化过程中，决定细胞自我更新或分化命运的bam基因表达受由Dpp、Tkv、pMad和Fused组成的复杂网络调控。我们前期关于该网络的研究表明系统在单稳态和双稳态间的分叉主要依赖于微环境信号Dpp强度变化。在本项目中，我们将进一步分析：（i）调控网络的稳态统计学特征，即系统各组分的表达噪声在网络中的传递以及与调控强度间的关系；（ii）当系统具有双稳态时，影响系统在两个稳态间转移速率的因素；（iii）Dpp的扩散动力学与干细胞分化的不可逆性，即Dpp在卵巢内沿“干细胞(GSC)-分化前体细胞(pre-CB)-分化细胞(CB)”方向的梯度分布及由Dpp受体Tkv与Fused拮抗作用所导致的果蝇生殖干细胞分化的不可逆性。

本项目研究发育生物学中早期动物胚胎发育的对称破缺的动态过程。我们发现胚胎发育的不均等分布起源于卵裂产生的分子随机差异，细胞分化调控出现了两种趋势：单稳模式，趋于消除差异；双稳模式，促进差异变大，出现两极分化，甚至出现“全或无”的分布。进一步发现，符合“双稳模式”的基因表达产物往往与细胞分化有关，揭示出“双稳模式”是引导早期卵裂出现命运分化的关键。项目执行期间共完成并发表学术论文6篇，均发表在SCI收录的期刊上。

内容获取失败，请点击重试