Multi-scale modeling uncovers 7q11.23 copy number variation-dependent alterations in ribosomal biogenesis, mTOR and neuronal maturation and excitability

Abstract

Copy number variation (CNV) at 7q11.23 causes Williams-Beuren (WBS) and 7q microduplication syndrome (7Dup), neurodevelopmental disorders featuring intellectual disability accompanied by symmetrically opposite neurocognitive features. Although significant progress has been made in understanding the molecular mechanisms underlying 7q11.23-related pathophysiology, the propagation of CNV dosage across gene expression layers and their interplay remains elusive. Here, we uncovered 7q11.23 dosage-dependent symmetrically opposite dynamics in neuronal differentiation and intrinsic excitability. By integrating transcriptomics, translatomics and proteomics of patient-derived and isogenic induced neurons, we found that genes related to neuronal transmission follow 7q11.23 dosage and are transcriptionally controlled, while translational factors and ribosomal genes are post-transcriptionally buffered. Consistently, we found phospho-RPS6 (pRPS6) down-regulated in WBS and up-regulated in 7Dup. Surprisingly, phospho-4EBP (p4EBP) was altered in the opposite direction reflecting dosage-specific changes in the total 4EBP levels. This highlights both different dosage-sensitive deregulations of the mTOR pathway as well as distinct roles of pRPS6 and p4EBP during neurogenesis. Our work demonstrates the importance of multi-scale disease modeling across molecular and functional layers and uncovers the pathophysiological relevance of ribosomal biogenesis in a paradigm pair of complex neurodevelopmental disorders and uncouples the roles of pRPS6 and p4EBPs as mechanistically actionable relays in neurodevelopmental disorders.