Embryonic origins of forebrain oligodendrocytes revisited by combinatorial genetic fate mapping

  1. Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Neurobiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China

Peer review process

Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, public reviews, and a response from the authors (if available).

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Editors

  • Reviewing Editor
    Samuel Pleasure
    University of California, San Francisco, San Francisco, United States of America
  • Senior Editor
    Sofia Araújo
    University of Barcelona, Barcelona, Spain

Reviewer #1 (Public Review):

Summary:

In this study, the authors generated a novel transgenic mouse line OpalinP2A-Flpo-T2A-tTA2 to specifically label mature oligodendrocytes, and at the same time their embryonic origins by crossing with a progenitor cre mouse line. With this clever approach, they found that LGE/CGE-derived OLs make minimum contributions to the neocortex, whereas MGE/POA-derived OLs make a small but lasting contribution to the cortex. These findings are contradictory to the current belief that LGE/CGE-derived OPCs make a sustained contribution to cortical OLs, whereas MGE/POA-derived OPCs are completely eliminated. Thus, this study provides a revised and more comprehensive view on the embryonic origins of cortical oligodendrocytes. To specifically label mature oligodendrocytes, and at the same time their embryonic origins by crossing with a progenitor cre mouse line. With this clever approach, they found that LGE/CGE-derived OLs make minimum contributions to the neocortex, whereas MGE/POA-derived OLs make a small-but-lasting contribution to to cortex. These findings are contradictory to the current belief that LGE/CGE-derived OPCs make a sustained contribution to cortical OLs, whereas MGE/POA-derived OPCs are completely eliminated. Thus, this study has provided a revised and updated view on the embryonic origins of cortical oligodendrocytes.

Strengths:

The authors have generated a novel transgenic mouse line to specifically label mature differentiated oligodendrocytes, which is very useful for tracing the final destiny of mature myelinating oligodendrocytes. Also, the authors carefully compared the distribution of three progenitor cre mouse lines and suggested that Gsh-cre also labeled dorsal OLs, contrary to the previous suggestion that it only marks LGE-derived OPCs. In addition, the author also analyzed the relative contributions of OLs derived from three distinct progenitor domains in other forebrain regions (e.g. Pir, ac). Finally, the new transgenic mouse lines and established multiple combinatorial genetic models will facilitate future investigations of the developmental origins of distinct OL populations and their functional and molecular heterogeneity.

Weaknesses:

Since OpalinP2A-Flpo-T2A-tTA2 only labels mature oligodendrocytes but not OPCs, the authors can not suggest that the lack of LGE/CGE-derived-OLs in the neocortex is less likely caused by competitive postnatal elimination, but more likely due to limited production and/or allocation (line 118-9). It remains possible that LGE/CGE-derived OPCs migrate into the cortex but are later eliminated.

Reviewer #2 (Public Review):

Summary:

In this manuscript, Cai et al use a combination of mouse transgenic lines to re-examine the question of the embryonic origin of telencephalic oligodendrocytes (OLs). Their tools include a novel Flp mouse for labelling mature oligodendrocytes and a number of pre-existing lines (some previously generated by the last author in Josh Huang's lab) that allowed combinatorial or subtractive labelling of oligodendrocytes with different origins. The conclusion is that cortically-derived OLs are the predominant OL population in the motor and somatosensory cortex and underlying corpus callosum, while the LGE/CGE generates OLs for the piriform cortex and anterior commissure rather than the cerebral cortex. Small numbers of MGE-derived OLs persist long-term in the motor, somatosensory and piriform cortex.

Strengths:

The strength and novelty of the manuscript lies in the elegant tools generated and used and which have the potential to elegantly and accurately resolve the issue of the contribution of different progenitor zones to telencephalic regions.

Weaknesses:

(1) Throughout the manuscript (with one exception, lines 76-78), the authors quantified OL densities instead of contributions to the total OL population (as a % of ASPA for example). This means that the reader is left with only a rough estimation of the different contributions.

(2) All images and quantifications have been confined to one level of the cortex and the potential of the MGE and the LGE/CGE to produce oligodendrocytes for more anterior and more posterior cortical regions remains unexplored.

(3) Hence, the statement that "In summary, our findings significantly revised the canonical model of forebrain OL origins (Figure 4A) and provided a new and more comprehensive view (Figure 4B )." (lines 111, 112) is not really accurate as the findings are neither new nor comprehensive. Published manuscripts have already shown that (a) cortical OLs are mostly generated from the cortex [Tripathi et al 2011 (https://doi.org/10.1523/JNEUROSCI.6474-10.2011), Winker et al 2018 (https://doi.org/10.1523/JNEUROSCI.3392-17.2018) and Li et al (https://doi.org/10.1101/2023.12.01.569674)] and (b) MGE-derived OLs persist in the cortex [Orduz et al 2019 (https://doi.org/10.1038/s41467-019-11904-4) and Li et al 2024 (https://doi.org/10.1101/2023.12.01.569674)]. Extending the current study to different rostro-caudal regions of the cortex would greatly improve the manuscript.

Reviewer #3 (Public Review):

In the manuscript entitled "Embryonic Origins of Forebrain Oligodendrocytes Revisited by Combinatorial Genetic Fate Mapping," Cai et al. used an intersectional/subtractional strategy to genetically fate-map the oligodendrocyte populations (OLs) generated from medial ganglionic eminence (NKX2.1+), lateral ganglionic eminences, and dorsal progenitor cells (EMX1+). Specifically, they generated an OL-expressing reporter mouse line OpalinP2A-Flpo-T2A-tTA2 and bred with region-specific neural progenitor-expressing Cre lines EMX1-Cre for dOL and NKX2.1-Cre for MPOL. They used a subtractional strategy in the OpalinFlp::Emx1Cre::Nkx2.1Cre::RC::FLTG mouse line to predict the origins of OLs from lateral/caudal ganglionic eminences (LC). With their genetic tools, the authors concluded that neocortical OLs primarily consist of dOLs. Although the populations of OLs (dOLs or MP-OLs) from Emx1+ or Nkx2.1+ progenitors are largely consistent with previous findings, they observed that MP-OLs contribute minimally but persist into adulthood without elimination as in the previous report (PMID: 16388308).

Intriguingly, by using an indirect subtraction approach, they hypothesize that both Emx1-negative and Nkx2.1-negative cells represent the progenitors from lateral/caudal ganglionic eminences (LC), and conclude that neocortical OLs are not derived from the LC region. This is in contrast to the previous observation for the contribution of LC-expressing progenitors (marked by Gsx2-Cre) to neocortical OLs (PMID: 16388308). The authors claim that Gsh2 is not exclusive to progenitor cells in the LC region (PMID: 32234482). However, Gsh2 exhibits high enrichment in the LC during early embryonic development. The presence of a small population of Gsh2-positive cells in the late embryonic cortex could originate/migrate from Gsh2-positive cells in the LC at earlier stages (PMID: 32234482). Consequently, the possibility that cortical OLs derived from Gsh2+ progenitors in LC could not be conclusively ruled out. Notably, a population of OLs migrating from the ventral to the dorsal cortical region was detected after eliminating dorsal progenitor-derived OLs (PMID: 16436615).

The indirect subtraction data for LC progenitors drawn from the OpalinFlp-tdTOM reporter in Emx1-negative and Nkx2.1-negative cells in the OpalinFlp::Emx1Cre::Nkx2.1Cre::RC::FLTG mouse line present some caveats that could influence their conclusion. The extent of activity from the two Cre lines in the OpalinFlp::Emx1Cre::Nkx2.1Cre::RC::FLTG mice remains uncertain. The OpalinFlp-tdTOM expression could occur in the presence of either Emx1Cre or Nkx2.1Cre, raising questions about the contribution of the individual Cre lines. To clarify, the authors should compare the tdTOM expression from each individual Cre line, OpalinFlp::Emx1Cre::RC::FLTG or OpalinFlp::Nkx2.1Cre::RC::FLTG, with the combined OpalinFlp::Emx1Cre::Nkx2.1Cre::RC::FLTG mouse line. This comparison is crucial as the results from the combined Cre lines could appear similar to only one Cre line active.

Overall, the authors provided intriguing findings regarding the origin and fate of oligodendrocytes from different progenitor cells in embryonic brain regions. However, further analysis is necessary to substantiate their conclusion about the fate of LC-derived OLs convincingly.

  1. Howard Hughes Medical Institute
  2. Wellcome Trust
  3. Max-Planck-Gesellschaft
  4. Knut and Alice Wallenberg Foundation