Congratulations to Caitlin!!! Her manuscript has been accepted at the Journal of Neuroscience! It's the culmination of a LOT of hard work over the last 4+ years, and she should be very proud of it! Thanks to Santiago and Brett for their work on the paper. A special thank you to our collaborators Odessa Yabut, Hector Gomez and Sam Pleasure from the Pleasure Lab at UCSF for a great collaboration.
The Dorsal Wave of Neocortical Oligodendrogenesis Begins Embryonically and Requires Multiple Sources of Sonic Hedgehog
Neural progenitor cells in the developing dorsal forebrain give rise to excitatory neurons, astrocytes and oligodendrocytes for the neocortex. Compared to neurons and astrocytes, less is known about the molecular mechanisms that instruct dorsal forebrain progenitors to an oligodendrocyte fate. In this study, we show that Sonic hedgehog (Shh) signaling is required in dorsal progenitors for their late embryonic transition to oligodendrogenesis. Using genetic lineage-tracing in mice of both sexes, we demonstrate that the majority of oligodendrocytes in the embryonic neocortex derive from Emx1+ dorsal forebrain progenitors. Deletion of the Shh signaling effector, Smo, specifically in Emx1+ progenitors led to significantly decreased oligodendrocyte numbers in the embryonic neocortex. Conversely, knockout of the Shh antagonist, Sufu, was sufficient to increase neocortical oligodendrogenesis.Using conditional knockout strategies, we found that Shh ligand is supplied to dorsal progenitors through multiple sources. Loss of Shh from Dlx5/6+ interneurons caused a significant reduction in oligodendrocytes in the embryonic neocortex. This phenotype was identical to that observed upon Shh deletion from the entire CNS using Nestin-Cre, indicating that interneurons migrating into the neocortex from the subpallium are the primary neural source of Shh for dorsal oligodendrogenesis. Additionally, deletion of Shh from migrating interneurons together with the choroid plexus epithelium led to a more severe loss of oligodendrocytes, suggesting that the choroid plexus is an important non-neural source of Shh ligand. Together, our studies demonstrate that the dorsal wave of neocortical oligodendrogenesis occurs earlier than previously appreciated, and requires highly regulated Shh signaling from multiple embryonic sources.