The Dorsal Wave of Neocortical Oligodendrogenesis Begins Embryonically and Requires Multiple Sources of Sonic Hedgehog

Abstract

Neural progenitor cells in the developing dorsal forebrain give rise to excitatory neurons, astrocytes, and oligodendrocytes for the neocortex. While we are starting to gain a better understanding about the mechanisms that direct the formation of neocortical neurons and astrocytes, far less is known about the molecular mechanisms that instruct dorsal forebrain progenitors to make oligodendrocytes. 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 most oligodendrocytes in the embryonic neocortex derive from Emx1 dorsal forebrain progenitors. Deletion of the Shh signaling effector specifically in Emx1 progenitors led to significantly decreased oligodendrocyte numbers in the embryonic neocortex. Conversely, knock-out of the Shh antagonist was sufficient to increase neocortical oligodendrogenesis. Using conditional knock-out strategies, we found that Shh ligand is supplied to dorsal progenitors through multiple sources. Loss of from Dlx5/6 interneurons caused a significant reduction in oligodendrocytes in the embryonic neocortex. This phenotype was identical to that observed upon deletion from the entire CNS using, indicating that interneurons migrating into the neocortex from the subpallium are the primary neural source of Shh for dorsal oligodendrogenesis. Additionally, deletion of 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. Most neocortical oligodendrocytes are made by neural progenitors in the dorsal forebrain, but the mechanisms that specify this fate are poorly understood. This study identifies Sonic hedgehog (Shh) signaling as a critical pathway in the transition from neurogenesis to oligodendrogenesis in dorsal forebrain progenitors during late embryonic development. The timing of this neuron-to-glia "switch" coincides with the arrival of migrating interneurons into the dorsal germinal zone, which we identify as a critical source of Shh ligand, which drives oligodendrogenesis. Our data provide evidence for a new model in which Shh signaling increases in the dorsal forebrain late in embryonic development to provide a temporally regulated mechanism that initiates the third wave of neocortical oligodendrogenesis.

Developmental dynamics of neurogenesis and gliogenesis in the postnatal mammalian brain in health and disease: Historical and future perspectives

“…In mouse embryonic telencephalon, cells in the OL lineage begin to emerge as early as E11.5, and these OPCs are continuously produced throughout the rest of embryogenesis and increase their number while migrating toward various brain regions, thereby becoming abundant and widespread already at birth (Goldman & Kuypers, 2015;Kessaris et al, 2006) (Figure 3a). Generation of new OPCs further continues during early postnatal stages, but they begin to cease cell divisions from the second postnatal week, and eventually differentiate into pre-OLs and OLs by the end of the first postnatal month (Crawford, Tripathi, Richardson, & Franklin, 2016;Kessaris et al, 2006;Marshall, Novitch, & Goldman, 2005;Parras et al, 2007;Tripathi et al, 2011;Winkler et al, 2018;Yue et al, 2006). In general, the transition from OPCs to pre-OLs and OLs proceeds in a ventro-caudal to dorso-rostral gradient in the mouse telencephalon, but the precise mechanisms that control the timing of their transitions in different regions of the brain remain largely unknown.…”

“…Early born OPCs start to emerge by E11.5 onward from ventral progenitor domains such as the preoptic area (POA) and median ganglionic eminence (MGE), and their generation subsequently spreads to a more dorsal domain called the lateral ganglionic eminence (LGE) at later embryonic stages (by E15.5) (Kessaris et al, 2006;Parras et al, 2007) (Figure 3a). In addition to these ventral domains, progenitors in the pallium (dorsal telencephalon) become a major source of OPCs at late embryonic (E18.5 onward) and early postnatal stages (Crawford et al, 2016;Marshall et al, 2005;Tripathi et al, 2011;Winkler et al, 2018;Yue et al, 2006). OPCs derived from ventral progenitor domains mainly populate the ventral aspect of the telencephalon, while those from both ventral and dorsal domains contribute to OLs that later myelinate axons in the dorsal telencephalon such as the neocortex and corpus callosum (CC) (Crawford et al, 2016;Kessaris et al, 2006;Marshall et al, 2005;Parras et al, 2007;Tripathi et al, 2011;Winkler et al, 2018;Yue et al, 2006).…”

Loss of Shh signaling in the neocortex reveals heterogeneous cell recovery responses from distinct oligodendrocyte populations

“…In the developing mouse forebrain, OPCs first appear in the ventral ventricular zones of the medial ganglionic and lateral ganglionic eminences in two temporal waves, and some of these cells migrate into the dorsal forebrain starting around E15.5 . A third wave of OPC production subsequently starts locally in the dorsal ventricular zone of the neocortex , and as early as E17.5 this dorsal population already makes up the vast majority of oligodendrocyte lineage cells in the neocortex (Winkler et al, 2018). Dorsally-derived cells continue to dominate in the mature neocortex, contributing 80-90% of all oligodendrocytes and OPCs (Tripathi et al, 2011;Winkler et al, 2018).…”

“…A third wave of OPC production subsequently starts locally in the dorsal ventricular zone of the neocortex , and as early as E17.5 this dorsal population already makes up the vast majority of oligodendrocyte lineage cells in the neocortex (Winkler et al, 2018). Dorsally-derived cells continue to dominate in the mature neocortex, contributing 80-90% of all oligodendrocytes and OPCs (Tripathi et al, 2011;Winkler et al, 2018). Thus, the neocortical oligodendrocyte lineage comprises a specific ratio of cells that originate from distinct ventral and dorsal forebrain regions.…”

“…The first two waves come from the ganglionic eminences in the ventral forebrain and the third wave is produced locally from neural progenitors in the dorsal forebrain Richardson et al, 2006). OPCs derived from ventral sources initially infiltrate and populate the developing neocortex, but are quickly outnumbered by dorsally-derived OPCs that ultimately contribute 80-90% of all oligodendrocytes and OPCs in the mature neocortex Tripathi et al, 2011;Winkler et al, 2018). The function of this ventral-to-dorsal switch is not yet known, nor are the mechanisms driving the exact ratios between the different sources.…”