Simultaneous production of diverse neuronal subtypes during early corticogenesis

Elia Magrinelli, Robin Jan Wagener, Denis Jabaudon

Preprint posted on July 16, 2018

How does the amazing diversity of cortical neurons emerge during development? A new preprint suggests that during early stages distinct types are simultaneously produced, while later on neuronal production is homogenous and sequential.

Selected by Boyan Bonev

Why is it important?

The cerebral cortex contains many different neuronal subtypes with distinctive morphology, connectivity and gene expression. Abnormal cortical development often translates into prominent neurodevelopmental and neuropsychiatric diseases, which affect different neuronal subtypes. How these neurons are produced in a precise sequence during embryonic development is one of the key questions in developmental neuroscience. Despite intense research in this area, the molecular mechanisms regulating the progression of molecular competence in cortical progenitors and how neuronal subtypes are produced temporally are still not well understood.

What are the key findings?

In this preprint Magrinelli and colleagues examine the fate of simultaneously-born cohorts of neurons at multiple stages during cortical development. To accomplish this, they utilize a high temporal resolution labeling technique, called FlashTag, which they combine with chronic administration of BrdU to distinguish between direct versus indirect neurogenesis. Using this approach, they uncover that at early stages of corticogenesis, there is an unexpected diversity in the molecular identity, laminar position and connectivity of simultaneously-born neurons. Conversely, later during embryonic development, the production of neurons is much more homogenous. Using retrograde labeling, the authors show that molecular differences in early-born neurons are also ultimately translated into laminar fate and connectivity. Finally, the authors suggest that at least some of the molecular diversity is postmitotic, as markers of different subtypes are progressively acquired during differentiation.

Diverse versus homogenous laminar fate and molecular identity of sequentially produced cortical neurons. Reposted from Magrinelli et al., bioRxiv 2018  with permission.

Questions arising

How much molecular diversity is encoded already in neural progenitors versus acquired postmitotically?

What are the molecular mechanisms for the progressive restriction of fate potential during corticogenesis?

What is the contribution of epigenetic modifications and post-transcriptional regulation to lineage specification in the cortex?


Related Research

Vitali I., et. al. & Jabaudon D. Progenitor Hyperpolarization Regulates the Sequential Generation of Neuronal Subtypes in the Developing Neocortex.  Cell (2018).

Govindan S. & Jabaudon D. Coupling progenitor and neuronal diversity in the developing neocortex.  FEBS Lett (2017).

Yuzwa SA. et. al., & Miller FD. Developmental Emergence of Adult Neural Stem Cells as Revealed by Single-Cell Transcriptional Profiling.  Cell Rep (2017)

Molyneaux B., Arlotta P., et al. & Macklis J. Neuronal subtype specification in the cerebral cortex.  Nat Rev Neurosci (2007)

Telley, L., et al. Sequential Transcriptional Waves Direct the Differentiation of Newborn Neurons in the Mouse Neocortex. Science 351, 1443–6 (2016).


Posted on: 29th August 2018

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  • Author's response

    Elia Magrinelli & Denis Jabaudon shared

    Response to Questions Arising:

    1. How much molecular diversity is encoded already in neural progenitors versus acquired postmitotically?
    • Elia Magrinelli (EM): This is a key point for which we don’t have a definitive answer. Using a limited set of molecular markers, we find that neuron type-specific characteristics are progressively implemented rather than present from their differentiation onset on, but differences involving other genes could be present early on just as well. A more comprehensive molecular analysis of simultaneously-born neurons throughout corticogenesis and at sequential stages of their differentiation would be required to answer this question.
    1. What are the molecular mechanisms for the progressive restriction of fate potential during corticogenesis?
    2. What is the contribution of epigenetic modifications and post-transcriptional regulation to lineage specification in the cortex?
    • EM: Well, one of the questions we are interested in in the lab is whether there is indeed a fate restriction, as opposed to “simply” a fate progression, as not much is yet known on this topic in mammals. In Drosophila, the seven-up gene regulates the progressive switch of specific neuroblasts cell autonomously during CNS development (Kanai et al. 2005), but external factors, including non-obviously genetic ones might be involved. We have recently shown for example that progression in the membrane potential of progenitors regulates their fate progression (Vitali et al., 2018). As for epigenetics and posttranscriptional aspects, this is an intense area of research right now. As techniques of tagging and isolating specific and coordinated subsets of differentiating neurons and progenitors become more efficient and available, epigenetic investigations on the subject could provide interesting outcomes.


    Response to additional questions

    1. Why did you pursue this study?
    • EMTime dependency in cortical development is a well-known concept, probably one of the first to be encountered while studying cortical development, although it is still relatively poorly understood in mammals. With FlashTag labeling, we were able to study this process with a high temporal resolution and thus decided to better characterize this process. We observed a substantial difference in the span of laminar distributions in early- vs. late-born neurons, which we thought was interesting because neurons in distinct cortical layers have distinct connectivities, functions and evolutionary histories.
    1. How is your method (i.e. Flashtag) better than existing approaches?
    • EMFlashTag allows specific labeling of isochronic/isocyclic cohorts of M-phase progenitors and their progeny. It is based on the fact that during cell division, that in neuronal birth, ventricular zone progenitors are transiently in contact with the ventricles, where FlashTag is injected and from where it diffuses inside cells (Telley et al. 2016, Govindan et al. 2018). This strategy thus allows to focus on the progeny of a population derived from a highly homogeneous population of progenitors. Nucleotide substitute pulse-labeling also has a high temporal resolution when in combination (Takahashi et al. 1999), but does not distinguish between distinct types of progenitors, rendering lineage analyses difficult.
    1. To what extend can the differences in diverse verse homogenous neuronal production can be explained by the switch from direct to indirect neurogenesis?
    • EMIt is actually unclear whether such a switch exists since indirect neurogenesis is present also at early stages of corticogenesis (Vitali et al. 2018, Càrdenas et al. 2018) but generally speaking yes, direct neurogenesis is more prevalent early on. But yes, it is possible that indirect neurogenesis acts to “buffer” stochastic differences in newborn neuron ground states, yielding more homogeneous final populations. Our labeling strategy selects for directly born neurons and depending on how strongly BP contribute to the final population at any given time, we might observe stronger differences between our labelling approach and previous nucleotide substitute pulse-labeling methods.
    1. Primates and humans are characterized by expanded upper cortical layers, do you think that upper-layer production can be less homogenous in those species compared to mice?
    • EMThe data we have on primate (including human) development suggests that expansion of the superficial layers results from an increase in the diversity of intermediate progenitor subtypes, thought to be reflected by the expansion of the outer subventricular zone. Seminal data from the Rakic lab (1974) using tritiated thymidine showed very sharply laminarly delineated populations of neurons following labeling at late embryonic stages (the high temporal resolution here is allowed by long developmental durations), so it seems like we would be getting the same type of results. Inter-areal differences might play a bigger role in species with large brains, which we haven’t examined here.
    1. What is your opinion on intrinsic versus extrinsic mechanisms for the progressive restriction of fate potential in cortical progenitors?
    • EMAgain, in the lab we think at this stage it is safer to talk about progression in fate potential rather than a restriction. The scientific literature contains examples of extrinsic and intrinsic mechanisms and both are likely involved, albeit to different extents at different stages of corticogenesis. With the advent of organoid preparations, it could soon be possible to better tease out this complex field.



    Kanai MI., et. al. & Hiromi Y. seven-up Controls switching of transcription factors that specify temporal identities of Drosophila neuroblasts.  Dev Cell (2005).

    Govindan, S, Oberst, P., and Jabaudon, D. In Vivo Pulse-Labeling of Isochronic Cohorts of Cells in the Central Nervous System Using FlashTag. bioRxiv, 286831 (2018).

    Takahashi, T., et al. Sequence of Neuron Origin and Neocortical Laminar Fate: Relation to Cell Cycle of Origin in the Developing Murine Cerebral Wall. J. Neurosci. 19, 10357–71 (1999).

    Telley, L., et al. Sequential Transcriptional Waves Direct the Differentiation of Newborn Neurons in the Mouse Neocortex. Science 351, 1443–6 (2016).

    Rakic P. Neurons in rhesus monkey visual cortex: Systematic relation between time of origin and eventual disposition. Science (1974)





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