Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Department of Neurobiology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Cell Rep. 2022 Feb 1;38(5):110307. doi: 10.1016/j.celrep.2022.110307.
The polarized flow of information through neural circuits depends on the orderly arrangement of neurons, their processes, and their synapses. This polarity emerges sequentially in development, starting with the directed migration of neuronal precursors, which subsequently elaborate neurites that form synapses in specific locations. In other organs, Fat cadherins sense the position and then polarize individual cells by inducing localized changes in the cytoskeleton that are coordinated across the tissue. Here, we show that the Fat-related protein Fat3 plays an analogous role during the assembly of polarized circuits in the murine retina. We find that the Fat3 intracellular domain (ICD) binds to cytoskeletal regulators and synaptic proteins, with discrete motifs required for amacrine cell migration and neurite retraction. Moreover, upon ICD deletion, extra neurites form but do not make ectopic synapses, suggesting that Fat3 independently regulates synapse localization. Thus, Fat3 serves as a molecular node to coordinate asymmetric cell behaviors across development.
信息通过神经回路的极化流动取决于神经元、它们的突起和突触的有序排列。这种极性在发育过程中是顺序出现的，从神经元前体的定向迁移开始，随后形成特定位置形成突触的神经突。在其他器官中，Fat 钙黏蛋白通过诱导细胞骨架的局部变化来感知位置，然后通过跨组织协调的方式使单个细胞极化。在这里，我们表明 Fat 相关蛋白 Fat3 在小鼠视网膜中极化回路的组装过程中发挥类似的作用。我们发现 Fat3 细胞内结构域 (ICD) 与细胞骨架调节剂和突触蛋白结合，需要离散的基序来进行无长突细胞的迁移和突起回缩。此外，在 ICD 缺失后，虽然形成了额外的神经突，但没有形成异位突触，这表明 Fat3 独立调节突触定位。因此，Fat3 作为一个分子节点，在发育过程中协调不对称细胞行为。
