Posttranscriptional Control of Neural Progenitors Temporal Dynamics During Neocortical Development by Syncrip

The development of the mammalian neocortex is precisely regulated by temporal gene expression, yet the temporal regulatory mechanisms of cortical neurogenesis, particularly how radial glial cells (RGCs) sequentially generate deep to superficial neurons, remain unclear. Here, the hnRNP family member Syncrip (hnRNP Q) is identified as a key modulator of superficial neuronal differentiation in neocortical neurogenesis. Syncrip knockout in RGCs disrupts differentiation and abnormal neuronal localization, ultimately resulting in superficial cortical layer defects as well as learning and memory impairments in mice. Single‐cell RNA sequencing analysis demonstrated that the knockout of Syncrip disrupts the late‐stage neurogenesis, stalling transcriptional progression in RGCs. Mechanistically, Syncrip maintains the transcription of temporal process‐related transcription factors by recruiting stabilization complexes through phase separation, crucially regulating the Notch signaling pathway that determines the fate of RGCs. Furthermore, pathogenic human mutations in Syncrip weaken its phase‐separation capability, failing to form stable complexes normally. Thus, Syncrip acts as a mediator of posttranscriptional regulatory mechanisms, governing the fate progression of RGCs and the advancement of intrinsic temporal programs. This study establishes an intracellular mechanism for posttranscriptional regulation of progressive fate determination in cortical neurogenesis. In this study, we aimed to elucidate Syncrip’s role in E14.5 neural progenitor cells (NPCs) and dorsal cortical development. To achieve this, we performed LACE-seq, RNA-seq, and scRNA-seq. LACE-seq was used to reveal direct RNA targets of Syncrip in cultured NPCs, RNA-seq captured global transcriptomic changes between WT and Syncrip cKO, and scRNA-seq provided single-cell-level insights into cellular diversity and differential gene expression within the developing dorsal telencephalon. By integrating these three datasets, we gained a comprehensive perspective on Syncrip-mediated post-transcriptional regulation, systemic transcriptional shifts, and cell-type-specific effects in the embryonic mouse cortex.