Decoding Cortical Glial Cell Development

Xiaosu Li,Zhejun Xu,Zhuangzhi Zhang,Zihao Su,Miao He,Ziwu Wang,Heng Du,Yangyang Duan,Guoping Liu,Yan You,Yuqun Cai,Lin Yang,Zhengang Yang,Haotian Chen,Qi Zhang,Zicong Shang,Bin Chen,Zhenmeiyu Li

doi:10.1007/s12264-021-00640-9

Abstract

Mouse cortical radial glial cells (RGCs) are primary neural stem cells that give rise to cortical oligodendrocytes, astrocytes, and olfactory bulb (OB) GABAergic interneurons in late embryogenesis. There are fundamental gaps in understanding how these diverse cell subtypes are generated. Here, by combining single-cell RNA-Seq with intersectional lineage analyses, we show that beginning at around E16.5, neocortical RGCs start to generate ASCL1+EGFR+ apical multipotent intermediate progenitors (MIPCs), which then differentiate into basal MIPCs that express ASCL1, EGFR, OLIG2, and MKI67. These basal MIPCs undergo several rounds of divisions to generate most of the cortical oligodendrocytes and astrocytes and a subpopulation of OB interneurons. Finally, single-cell ATAC-Seq supported our model for the genetic logic underlying the specification and differentiation of cortical glial cells and OB interneurons. Taken together, this work reveals the process of cortical radial glial cell lineage progression and the developmental origins of cortical astrocytes and oligodendrocytes.

Highlights

The mammalian cerebral cortex, controlling the highest brain functions, contains billions of neurons and glia
Around E16.5, cortical radial glial cells (RGCs) start to generate ASCL1?EGFR? apical multipotent IPCs (MIPCs) in the ventricular zone (VZ) and subventricular zone (SVZ). aMIPCs quickly differentiate into basal MIPCs that express ASCL1, EGFR, OLIG2, and MKI67. bMIPCs undergo several rounds of divisions to generate cortical oligodendrocytes, astrocytes, and OB interneurons (OBiNs). Those RGCs that are translocating to the cortex and transforming into AS-intermediate progenitor cells (IPCs) in late embryogenesis express ASCL1, EGFR, and OLIG2
Our scRNA-Seq analysis revealed that neocortical RGCs in late embryogenesis first generated aMIPCs, which quickly differentiated into bMIPCs, and most OPCs, astrocyte lineage-restricted progenitor cells (AS-IPCs), and OBiN-IPCs went through this bMIPC state before their cell fates were committed

Summary

Introduction

The mammalian cerebral cortex, controlling the highest brain functions, contains billions of neurons and glia. Oligodendrocytes and astrocytes are macroglial cells, the most abundant cell type in the cortex We know that these glial cells perform key functions vital to the physiology of the cerebral cortex. We do not know how cortical oligodendrocytes, astrocytes, and OBiNs are produced from RGCs; especially, a precise understanding of astrocyte lineage-restricted progenitor cells (AS-IPCs) and its developmental process are lacking. BMIPCs undergo several rounds of divisions to generate cortical oligodendrocytes, astrocytes, and OBiNs. Briefly, around E16.5, cortical RGCs start to generate ASCL1?EGFR? AMIPCs quickly differentiate into basal MIPCs (bMIPCs) that express ASCL1, EGFR, OLIG2, and MKI67. BMIPCs undergo several rounds of divisions to generate cortical oligodendrocytes, astrocytes, and OBiNs Those RGCs that are translocating to the cortex and transforming into AS-IPCs in late embryogenesis express ASCL1, EGFR, and OLIG2. This work reveals the process of cortical RGC lineage progression and the developmental origins of cortical astrocytes and oligodendrocytes

Materials and Methods

Results

Discussion