Cortical GABAergic inhibitory interneurons have crucial roles in the development and function of the cerebral cortex. In rodents, nearly all neocortical interneurons are generated from the subcortical ganglionic eminences. In humans and nonhuman primates, however, the developmental origin of neocortical GABAergic interneurons remains unclear. Here we show that the expression patterns of several key transcription factors in the developing primate telencephalon are very similar to those in rodents, delineating the three main subcortical progenitor domains (the medial, lateral and caudal ganglionic eminences) and the interneurons tangentially migrating from them. On the basis of the continuity of Sox6, COUP-TFII and Sp8 transcription factor expression and evidence from cell migration and cell fate analyses, we propose that the majority of primate neocortical GABAergic interneurons originate from ganglionic eminences of the ventral telencephalon. Our findings reveal that the mammalian neocortex shares basic rules for interneuron development, substantially reshaping our understanding of the origin and classification of primate neocortical interneurons.

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.

Cortical GABAergic interneurons in rodents originate from subpallial progenitors and tangentially migrate to the cortex. While the majority of mouse neocortical interneurons are derived from the medial and caudal ganglionic eminence (MGE and CGE, respectively), it remains unknown whether the lateral ganglionic eminence (LGE) also contributes to a subpopulation of cortical interneurons. Here, we show that the transcription factor Sp8 is expressed in one-fifth of adult cortical interneurons, which appear to be derived from both the dorsal LGE and the dorsal CGE (dLGE and dCGE, respectively). Compared with the MGE-derived cortical interneurons, dLGE/dCGE-derived Sp8-expressing (Sp8+) ones are born at later embryonic stages with peak production occurring at embryonic day 15.5. They tangentially migrate mainly along the subventricular/intermediate zone (SVZ/IZ) route; some continue to express mitotic markers (Ki67 and PH3) in the neonatal cortical SVZ/IZ. Sp8+ interneurons continue to radially migrate from the SVZ/IZ into the cortical layers at early postnatal stages. In contrast to MGE-derived interneurons, dLGE/dCGE-derived Sp8+ interneurons follow an outside-in layering pattern, preferentially occupying superficial cortical layers.

The Nedd4 family E3 ligases are key regulators of cell growth and proliferation and are often misregulated in human cancers and other diseases. The ligase activities of Nedd4 E3s are tightly controlled via auto-inhibition. However, the molecular mechanism underlying Nedd4 E3 auto-inhibition and activation is poorly understood. Here, we show that the WW domains proceeding the catalytic HECT domain play an inhibitory role by binding directly to HECT in the Nedd4 E3 family member Itch. Our structural and biochemical analyses of Itch reveal that the WW2 domain and a following linker allosterically lock HECT in an inactive state inhibiting E2-E3 transthiolation. Binding of the Ndfip1 adaptor or JNK1-mediated phosphorylation relieves the auto-inhibition of Itch in a WW2-dependent manner. Aberrant activation of Itch leads to migration defects of cortical neurons during development. Our study provides a new mechanism governing the regulation of Itch.