来自耶鲁大学分子、细胞与发育生物学系，神经系统科学系间计划（Interdepartmental Neuroscience Program）的研究人员在Numb信号途径研究过程中发现ACBD3扮演的协同作用，为神经细胞发生与分化的研究提供了新的突破口。这一研究成果发表在4月6日的《细胞》（Cell）杂志上。
领导这一研究的是耶鲁大学的钟伟民博士，其2006年被聘为东南大学“客座研究员” ，在分子细胞发育生物学研究领域成绩斐然，有关“不对称的细胞分裂与干细胞”和“动物神经发育”方面的研究成果多次发表在《自然》（Nature）等国际权威杂志。
细胞不对称分裂产生两个不同命运的子细胞，是细胞多样性形成的基础。哺乳动物神经前体细胞不对称分裂成自我保持（self-renew）状态，并通过隔离胞质中Numb蛋白形成一个神经元。其中膜相关蛋白Numb是细胞命运决定因子：在细胞有丝分裂期，Numb选择性地分布于细胞的一侧。在胞质分裂后则被分配于一个子细胞，这样Numb通过抑制跨膜受体Notch而发挥作用。
Numb信号途径在前体细胞的神经元调控方面起着重要作用，但是令人觉得矛盾的是，Numb也促进神经元的分化。在这篇文章中，研究人员发现ACBD3在细胞分化过程中扮演着Numb partner的角色，ACBD3与Numb蛋白通过Numb一个结构域相互作用，而功能失活突变（loss-of-function mutation，LOF）和功能激活突变（gain-of-function mutation，GOD）小鼠表型相似。有趣的是，在神经元和interphase progenitor cells中ACBD3与高尔基体相关，但在有丝分裂高尔基体分裂之后，ACBD3会呈现出cytosolic，这时也需要Numb来区分两个子细胞。
因此，研究人员认为，胞质中的ACBD3可以与Numb一道特化细胞的命运，而其在前体细胞循环中的持续出现则抑制了神经元的产生。细胞周期中高尔基体的分裂和重新构建通过ACBD3亚细胞分配分别调控了Numb信号，这也说明了一种链接细胞命运发生和细胞周期进阶的机制。
Cell, Vol 129, 163-178, 06 April 2007
Article
The Mammalian Golgi Regulates Numb Signaling in Asymmetric Cell Division by Releasing ACBD3 during Mitosis
Yan Zhou,1 Joshua B. Atkins,1,2 Santiago B. Rompani,1,3 Daria L. Bancescu,1 Petur H. Petersen,1,4 Haiyan Tang,1,2,5 Kaiyong Zou,1 Sinead B. Stewart,1 and Weimin Zhong1,2,
1 Department of Molecular, Cellular, and Developmental Biology, Yale University, P.O. Box 208103, New Haven, CT 06520, USA
2 Interdepartmental Neuroscience Program, Yale University, P.O. Box 208103, New Haven, CT 06520, USA
Corresponding author
Weimin Zhong
weimin.zhong@yale.edu
Summary
Mammalian neural progenitor cells divide asymmetrically to self-renew and produce a neuron by segregating cytosolic Numb proteins primarily to one daughter cell. Numb signaling specifies progenitor over neuronal fates but, paradoxically, also promotes neuronal differentiation. Here we report that ACBD3 is a Numb partner in cell-fate specification. ACBD3 and Numb proteins interact through an essential Numb domain, and the respective loss- and gain-of-function mutant mice share phenotypic similarities. Interestingly, ACBD3 associates with the Golgi apparatus in neurons and interphase progenitor cells but becomes cytosolic after Golgi fragmentation during mitosis, when Numb activity is needed to distinguish the two daughter cells. Accordingly, cytosolic ACBD3 can act synergistically with Numb to specify cell fates, and its continuing presence during the progenitor cell cycle inhibits neuron production. We propose that Golgi fragmentation and reconstitution during cell cycle differentially regulate Numb signaling through changes in ACBD3 subcellular distribution and represent a mechanism for coupling cell-fate specification and cell-cycle progression.
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