Integrative analysis of the embryonic origin of adult neural stem cells in forebrain subventricular zones

In the mammalian brain, adult neural stem cells (NSCs) located in ventricular-subventricular zone (V-SVZ) of lateral ventricles and dentate gyrus continuously generate new neurons and glia throughout life. The adult NSCs in V-SVZ are derived from ventricular radial glial cells (RGCs) which become quiescent during embryonic development. However, the origin and establishment of this adult NSC pool remain elusive, primarily due to the challenge of tracing the lineage from embryonic RGCs to their quiescent adult successors. Here, by leveraging Vcam1—a marker continuously expressed from embryonic RGCs to adult NSCs—we unravel the dynamic process and regulatory mechanism underlying the fate bifurcation that gives rise to quiescent seed cells. We demonstrate that Vcam1+ embryonic RGCs directly contribute to the adult NSC pool. A subpopulation of quiescent Vcam1+ RGCs emerges early and is maintained throughout development, while a parallel population of proliferative Vcam1+ progenitors actively replenishes this quiescent reservoir. Through the combinatory analysis of single-cell multi-omics and clonal lineage tracing of Vcam1+ cells, we identified the TGF-β/Smad3 pathway as a critical regulator of quiescence. Our work thus provides a mechanistic dissection of how the foundational adult NSC pool is established through precisely regulated fate decisions during embryogenesis, offering new insights into the principles of lifelong neurogenesis.