Differential Hes1 activation defines neural stem cell lineage commitment and niche maintenance in embryonic and adult mouse cortex

PNAS

January 20, 2026 | 123 (4) e2511800123 DOI: 10.1073/pnas.2511800123

Paul Ann Riya, Rahul Jose, Vadakkath Meera, Budhaditya Basu, Suresh Surya, Ramankunju Aryasree, Nair Pradeep Jyothi, Surendran Parvathy, Sivadasan Bindu Dhanesh, Rajendran Sanalkumar, Viviane Praz, Nicolo Riggi, Jackson James

Abstract

Mode of Hes1 activation and its differential expression are crucial for the maintenance of neural stem cells/progenitor cells (NSCs/NPCs) in the embryonic cortex. This differential mode of Hes1 activation has been translated into a heterogeneous population of NSCs comprising Notch-independent Hes1-expressing (NIHes1) NSCs and Notch-dependent Hes1-expressing (NDHes1) radial glial cells (RGCs). Using single-cell transcriptomics and a Nestin-CreERT2;NIHes1^fl/fl conditional knock-out mouse model, we have characterized the NIHes1 NSCs. Our analyses show that NIHes1 NSCs are the ancestral precursor NSCs that generate RGCs and intermediate progenitor cells during development. Loss of NIHes1 expression significantly alters the NSC niche, leading to increased gliogenesis and aberrant migration of projection neurons. NIHes1 NSCs are set aside at embryonic stages as adult neural stem cells and are maintained by NIHes1 expression even at adult stage. Our findings suggest that NIHes1 NSCs are functionally distinct Hes1-expressing NSCs, which are critical for establishing both embryonic and adult NSC niches, thereby contributing to the overall cortical development.