3/7 TLDR: we use in vivo CRISPR+whole-brain imaging to capture cytoarchitectures📸 Transcriptional signal alone does not reliably predict structural outcomes. To understand how disease genes reshape the circuit, we need multimodal readouts on molecular state + cellular form!
2/7 Many of us ask how genetics reshapes the brain at the level of cellular structure. We now can profile molecular outcomes w scRNAseq at scale, but morphology - especially long-range cytoarchetecture - has remained much harder to measure systematically in pooled screens in vivo
4/7 We mapped how structure changes over time in WT neurons and related those dynamics to RNA programs, revealing coordinated and highly structured remodeling e.g. ASD risk genes were enriched in “stabilizing” program, pointing to an early postnatal window of vulnerability
Excited to share Keystone on Neurodevelopmental Disorders in Colorado Jan 2027! ⛷️
with Tom Nowakowski, Stephan Sanders & Joe Zhou
🌟Amazing lineup keynotes from Allyson Berent & Huda Zoghbi! ⏰Abstracts/scholarship due 9/24, Poster abstract due 9/29
Join us: keystonesymposia.org/conferences/...
Form follows function, or function dictates form?
📢Preprint: we build Perturb-CLEAR, in vivo screen of neuroanatomy! Disease perturbations produce selective morphology-RNA changes that RNA impact alone cannot predict. Was led by the invincible grad student Boli Wu!
www.biorxiv.org/content/10.6...
5/7 We then applied Perturb-CLEAR to KO neurodevelopmental disorder genes and found perturbation effects were not uniform: Different genes produced distinct outcomes, with specific vulnerabilities emerging across cell types and across different parts of dendritic architecture
6/7 Paired in vivo Perturb-seq revealed matched molecular phenotypes, allowing us to ask when transcriptional disruption propagates into structural remodeling. In some cases, the two modalities aligned strongly; in others, molecular change and structural outcome diverged
7/7 We hope Perturb-CLEAR helps connect genomics & neuroanatomy: how mutations reshape circuit-relevant cytoarchitecture in disease: multimodal data matters!
Thank you Joshua Levin, William Yang, awesome collaborators & team, especially the phenomenal Boli Wu leading this! -FIN-
These rankings are kinda silly… but hey, we’re #1 🍾🥂🥳
Xin Jin FTW!
"We developed Perturb-CLEAR, which integrates pooled CRISPR screening and whole-mount imaging to quantify brain-wide cytoarchitecture, and paired it with Perturb-seq to link structural phenotypes to transcriptomic changes."
www.biorxiv.org/content/10.6...
