Ly Phuong Thao, Wang Hongyan
Neuroscience & Behavioral Disorders Programme, Duke-NUS Medical School, Singapore, Singapore.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Front Cell Dev Biol. 2020 Feb 11;8:60. doi: 10.3389/fcell.2020.00060. eCollection 2020.
How stem cells and progenitors balance between self-renewal and differentiation is a central issue of stem cell biology. Here, we describe a novel and essential function of Fzr/Cdh1, an evolutionary conserved protein, during the differentiation of neural stem cell (NSC) lineages in the central nervous system. We show that Fzr, a known co-activator of Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin ligase, promotes the production of neurons from neural progenitors called ganglion mother cells (GMCs). However, knockdown of APC/C subunit or another APC/C co-activator does not similarly impair GMC-neuron transition. We also observe a concomitant loss of differentiation factor Prospero expression and ectopic accumulation of mitotic kinase Polo in mutant clones, strongly supporting the impairment of GMC to neuron differentiation. Besides functioning in GMCs, Fzr is also present in NSCs to facilitate the production of intermediate neural progenitors from NSCs. Taken together, Fzr plays a novel function in promoting differentiation programs during NSC lineage development. Given that human Fzr is inactivated in multiple types of human cancers including brain tumors and that Fzr regulates neurotoxicity in various models of neurodegenerative diseases, our study on the role of Fzr in turning off proliferation in neuronal cells may provide insights into how Fzr deficits may contribute to human neurodegenerative diseases and tumors.
干细胞和祖细胞如何在自我更新和分化之间保持平衡是干细胞生物学的核心问题。在此，我们描述了一种进化保守蛋白Fzr/Cdh1在中枢神经系统神经干细胞（NSC）谱系分化过程中的新的重要功能。我们发现，Fzr是后期促进复合物/细胞周期体（APC/C）泛素连接酶的已知共激活因子，它能促进神经祖细胞（称为神经节母细胞，GMCs）产生神经元。然而，敲低APC/C亚基或另一种APC/C共激活因子并不会同样损害GMC向神经元的转变。我们还观察到在突变克隆中分化因子Prospero表达的同时丧失以及有丝分裂激酶Polo的异位积累，这有力地支持了GMC向神经元分化的受损。除了在GMCs中发挥作用外，Fzr也存在于NSCs中，以促进NSCs产生中间神经祖细胞。综上所述，Fzr在NSC谱系发育过程中促进分化程序方面发挥了新的功能。鉴于人类Fzr在包括脑肿瘤在内的多种人类癌症中失活，并且Fzr在各种神经退行性疾病模型中调节神经毒性，我们对Fzr在关闭神经元细胞增殖中作用的研究可能为Fzr缺陷如何导致人类神经退行性疾病和肿瘤提供见解。
