Cell-Cell Signaling In Embryonic and Retinal Development

 描述（由申请人提供）：细胞命运最初是如何被指定的，然后在随后的终末分化过程中稳定维持的问题对于理解正常发育进程和改变细胞命运或使细胞命运不稳定的疾病机制具有根本重要性。虽然信号机制和分子，指定个别细胞的命运已经被广泛研究，少得多的是已知的途径和相互作用，保持这些命运稳定或有关的时间和程度，不同的细胞状态成为锁定在终端分化的进行。这个目标 这项研究的目的是阐明果蝇视觉系统发育过程中感光细胞命运稳定的遗传机制。果蝇视网膜提供了一个非常易于处理和定义明确的实验模型，在发现跨物种广泛保守的新遗传机制方面有着良好的记录。特别是，苍蝇视网膜的定型模式和结构有利于识别和跟踪个体细胞类型的空间和时间，丰富的可用标记物允许详细评估细胞命运。由于信号传导机制已被证明是非常保守的，我们确定的分子网络和相互作用，稳定视网膜细胞的命运在苍蝇可能是相关的哺乳动物的发展。因此，我们研究果蝇视网膜神经元的去分化和转分化的工作可能会确定保守的信号传导机制，最终可以利用这些机制来修复因退行性疾病或灾难性损伤而受损的人体组织。目的1探讨Abelson非受体酪氨酸激酶在维持果蝇光感受器神经元终末分化状态中的遗传需求。我们将测试的假设，Abl是需要稳定光感受器的命运，并定义其功能所需的发育窗口。我们将询问Abl是否在这种情况下与其典型的信号伴侣相互作用，或者Abl是否与其典型的信号伴侣相互作用。 通过新的机制发挥作用。目的2将探讨Abelson介导的Notch信号抑制对于维持光感受器命运至关重要的假设。实验将研究异位Notch信号传导对Abl突变体中神经元标志物表达丧失的贡献，并将评估Notch信号传导的异位激活诱导视网膜中神经元去分化的充分性。目的3将研究在终末分化过程中稳定/不稳定感光细胞命运的信号机制。使用候选基因方法和遗传筛选的组合，我们将确定与Abl和Notch信号相互作用以稳定视网膜中细胞命运的遗传电路。我们将探讨类似的信号机制是否同样稳定/不稳定细胞在其他组织的命运。

 DESCRIPTION (provided by applicant): The question of how cell fates are initially specified and then stably maintained during subsequent terminal differentiation is of fundamental importance to understanding both normal developmental progression and disease mechanisms that transform or destabilize cell fates. Whereas signaling mechanisms and molecules that specify individual cell fates have been studied extensively, much less is known either about the pathways and interactions that maintain these fates stably or about the timing and extent to which different cell states become locked in as terminal differentiation proceeds. The goal of this proposal is to elucidate the genetic mechanisms that stabilize photoreceptor cell fate in the developing Drosophila visual system. The fly retina provides a superbly tractable and well-defined experimental model, with a proven track record in uncovering novel genetic mechanisms that are broadly conserved across species. In particular, the stereotyped patterning and architecture of the fly retina facilitates the identification and tracking of indiviual cell types over space and time, and the wealth of available markers permits detailed assessment of cell fates. Because signaling mechanisms have proven to be extraordinarily conserved, our identification of molecular networks and interactions that stabilize retinal cell fates in the fly are likely to be relevant to mammalian development. Thus our work studying dedifferentiation and transdifferentiation of Drosophila retinal neurons may identify conserved signaling mechanisms that could eventually be harnessed to repair human tissues damaged by degenerative disease or catastrophic injury. Aim 1 will explore the genetic requirement for the Abelson nonreceptor tyrosine kinase in maintaining the terminally differentiated state of Drosophila photoreceptor neurons. We will test the hypothesis that Abl is required to stabilize photoreceptor fate and define the developmental window in which its function is required. We will ask whether Abl interacts with its canonical signaling partners in this context, or whether it acts through novel mechanisms. Aim 2 will explore the hypothesis that Abelson-mediated inhibition of Notch signaling is critical for maintenance of photoreceptor fate. Experiments will investigate the contribution of ectopic Notch signaling to loss of neuronal marker expression in Abl mutants, and will assess the sufficiency of ectopic activation of Notch signaling to induce neuronal dedifferentiation in the retina. Aim 3 will investigate the signaling mechanisms that stabilize/destabilize photoreceptor fates during terminal differentiation. Using a combination of candidate gene approaches and genetic screens, we will identify the genetic circuitries that interact with Abl and Notch signaling to stabilize cell fates in the retina. We will explore whethe analogous signaling mechanisms similarly stabilize/destabilize cell fates in other tissues.