(A) Schematic of approach to tag endogenous proteins in neurons using HiUGE. Cultured hippocampal neurons were infected on DIV0 with AAVs containing the candidate sgRNA and a 2x-HA-V5-Myc HiUGE donor in the corresponding open reading frame. Neurons expressing a GFP cell fill were used as a control. (B) Quantification of presynaptic enrichment for GFP control (n=6 neurons), presynaptic marker Syn1 (Synapsin1, n=5), and candidate proteins (Abi2 n=6, Add1 n=5, Ctnnd2 n=5, Cttn n=5, Cttnbp2 n=5, Cyfip2 n=5, Dmtn n=5, Fam171b n=5, Lasp1 n=5, Nwd2 n=5, Ppp1r9b n=5, Tagln3 n=6, Trio n=5, Wipf3 n=6); one-way ANOVA (F15,68=5.401, p<0.0001) with Dunnett’s multiple comparisons test vs GFP: Syn1 (p<0.0001), Abi2 (p=0.0422), Add1 (p=0.0088), Ctnnd2 (p<0.0001), Cttn (p<0.0001), Cttnbp2 (p=0.0008), Cyfip2 (p=0.0032), Dmtn (p=0.0010), Fam171b (p=0.0215), Lasp1 (p=0.0156), Nwd2 (p<0.0001), Ppp1r9b (p=0.0030), Tagln3 (p=0.0437), Trio (p=0.0016), Wipf3 (p=0.0359). (C–Q) Representative images of the localization of candidate proteins (HA/V5/Myc or GFP; green) and a presynaptic marker (Synapsin1; magenta). Scale bars, 50 μm. Insets show staining along axons. The merged image contains only Synapsin1 puncta within the axon, and white arrows point to presynaptic terminals (colocalized puncta). Scale bars, 5 μm. All data are mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.
Figure 2—source data 1. Candidate genes screened for HiUGE validation of the Synapsin iBioID proteome.