Takeo Yukari H, Shuster S Andrew, Jiang Linnie, Hu Miley C, Luginbuhl David J, Rülicke Thomas, Contreras Ximena, Hippenmeyer Simon, Wagner Mark J, Ganguli Surya, Luo Liqun
Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Neurosciences Program, Stanford University, Stanford, CA 94305, USA.
Neuron. 2021 Feb 17;109(4):629-644.e8. doi: 10.1016/j.neuron.2020.11.028. Epub 2020 Dec 21.
The synaptotrophic hypothesis posits that synapse formation stabilizes dendritic branches, but this hypothesis has not been causally tested in vivo in the mammalian brain. The presynaptic ligand cerebellin-1 (Cbln1) and postsynaptic receptor GluD2 mediate synaptogenesis between granule cells and Purkinje cells in the molecular layer of the cerebellar cortex. Here we show that sparse but not global knockout of GluD2 causes under-elaboration of Purkinje cell dendrites in the deep molecular layer and overelaboration in the superficial molecular layer. Developmental, overexpression, structure-function, and genetic epistasis analyses indicate that these dendrite morphogenesis defects result from a deficit in Cbln1/GluD2-dependent competitive interactions. A generative model of dendrite growth based on competitive synaptogenesis largely recapitulates GluD2 sparse and global knockout phenotypes. Our results support the synaptotrophic hypothesis at initial stages of dendrite development, suggest a second mode in which cumulative synapse formation inhibits further dendrite growth, and highlight the importance of competition in dendrite morphogenesis.
突触营养假说认为，突触形成可稳定树突分支，但这一假说尚未在哺乳动物大脑中进行活体因果检验。突触前配体小脑素-1（Cbln1）和突触后受体GluD2介导小脑皮质分子层中颗粒细胞与浦肯野细胞之间的突触形成。在此，我们表明，GluD2的稀疏而非整体敲除会导致深层分子层中浦肯野细胞树突发育不足，而在浅层分子层中则过度发育。发育、过表达、结构功能和遗传上位性分析表明，这些树突形态发生缺陷是由Cbln1/GluD2依赖性竞争相互作用不足所致。基于竞争性突触形成的树突生长生成模型在很大程度上概括了GluD2稀疏和整体敲除表型。我们的结果支持树突发育初始阶段的突触营养假说，提示了累积突触形成抑制树突进一步生长的第二种模式，并突出了竞争在树突形态发生中的重要性。
