Program for Neuroscience and Mental Health, Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Program for Neuroscience and Mental Health, Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Curr Biol. 2024 Sep 23;34(18):4224-4239.e4. doi: 10.1016/j.cub.2024.08.002. Epub 2024 Aug 29.
Neurons form cell-type-specific morphologies that are shaped by cell-surface molecules and their cellular events governing dendrite growth. One growth rule is dendrite self-avoidance, whereby dendrites distribute uniformly within a neuron's territory by avoiding sibling branches. In mammalian neurons, dendrite self-avoidance is regulated by a large family of cell-recognition molecules called the clustered protocadherins (cPcdhs). Genetic and molecular studies suggest that the cPcdhs mediate homophilic recognition and repulsion between self-dendrites. However, this model has not been tested through direct investigation of self-avoidance during development. Here, we performed live imaging and four-dimensional (4D) quantifications of dendrite morphogenesis to define the dynamics and cPcdh-dependent mechanisms of self-avoidance. We focused on the mouse retinal starburst amacrine cell (SAC), which requires the gamma-Pcdhs (Pcdhgs) and self/non-self-recognition to establish a stereotypic radial morphology while permitting dendritic interactions with neighboring SACs. Through morphogenesis, SACs extend dendritic protrusions that iteratively fill the growing arbor and contact and retract from nearby self-dendrites. Compared to non-self-contacting protrusions, self-contacting events have longer lifetimes, and a subset persists as loops. In the absence of the Pcdhgs, non-self-contacting dynamics are unaffected but self-contacting retractions are significantly diminished. Self-contacting bridges accumulate, leading to the bundling of dendritic processes and disruption to the arbor shape. By tracking dendrite self-avoidance in real time, our findings establish that the γ-Pcdhs mediate self-recognition and retraction between contacting sibling dendrites. Our results also illustrate how self-avoidance shapes stochastic and space-filling dendritic outgrowth for robust pattern formation in mammalian neurons.
神经元形成细胞类型特异性形态，这些形态受细胞表面分子及其控制树突生长的细胞事件的影响。一个生长规则是树突自回避，即树突通过避免兄弟姐妹分支在神经元的区域内均匀分布。在哺乳动物神经元中，树突自回避受称为聚集原钙黏蛋白（cPcdhs）的大量细胞识别分子家族调节。遗传和分子研究表明，cPcdhs 介导同源识别和自我树突之间的排斥。然而，这个模型尚未通过在发育过程中对自回避进行直接研究来测试。在这里，我们进行了活细胞成像和四维（4D）定量分析，以定义自回避的动力学和 cPcdh 依赖性机制。我们专注于小鼠视网膜星爆无长突细胞（SAC），它需要γ-Pcdhs（Pcdhgs）和自我/非自我识别来建立一种典型的放射状形态，同时允许树突与相邻 SAC 相互作用。通过形态发生，SAC 延伸树突突起，这些突起反复填充正在生长的树突，并与附近的自我树突接触和缩回。与非自我接触的突起相比，自我接触的事件具有更长的寿命，并且子集作为环持续存在。在没有 Pcdhgs 的情况下，非自我接触的动力学不受影响，但自我接触的缩回明显减少。自我接触的桥接物积累，导致树突过程的捆绑和树突形状的破坏。通过实时跟踪树突自回避，我们的发现确立了 γ-Pcdhs 介导接触的兄弟姐妹树突之间的自我识别和缩回。我们的结果还说明了自回避如何为哺乳动物神经元中的稳健模式形成塑造随机和空间填充的树突生长。
