Menu

Close

Simultaneous production of diverse neuronal subtypes during early corticogenesis

Elia Magrinelli, Robin Jan Wagener, Denis Jabaudon

Preprint posted on July 16, 2018 https://www.biorxiv.org/content/early/2018/07/16/369678

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

Read preprint (No Ratings Yet)




  • 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.

     

    References:

    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)

     

     

     

     

    Have your say

    Your email address will not be published. Required fields are marked *

    This site uses Akismet to reduce spam. Learn how your comment data is processed.

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    Also in the developmental biology category:

    Single cell RNA-Seq reveals distinct stem cell populations that drive sensory hair cell regeneration in response to loss of Fgf and Notch signaling

    Mark E. Lush, Daniel C. Diaz, Nina Koenecke, et al.

    AND

    Distinct progenitor populations mediate regeneration in the zebrafish lateral line.

    Eric D Thomas, David Raible



    Selected by Rudra Nayan Das

    1

    Force inference predicts local and tissue-scale stress patterns in epithelia

    Weiyuan Kong, Olivier Loison, Pruthvi Chavadimane Shivakumar, et al.



    Selected by Sundar Naganathan

    Embryo geometry drives formation of robust signaling gradients through receptor localization

    Zhechun Zhang, Steven Zwick, Ethan Loew, et al.



    Selected by Diana Pinheiro

    Unlimited genetic switches for cell-type specific manipulation

    Jorge Garcia-Marques, Ching-Po Yang, Isabel Espinosa-Medina, et al.



    Selected by Rafael Almeida

    1

    Applications, Promises, and Pitfalls of Deep Learning for Fluorescence Image Reconstruction

    Chinmay Belthangady , Loic A. Royer



    Selected by Romain F. Laine

    Maintenance of spatial gene expression by Polycomb-mediated repression after formation of a vertebrate body plan

    Julien Rougot, Naomi D Chrispijn, Marco Aben, et al.



    Selected by Yen-Chung Chen

    1

    The coordination of terminal differentiation and cell cycle exit is mediated through the regulation of chromatin accessibility

    Yiqin Ma, Daniel J McKay, Laura Buttitta



    Selected by Gabriel Aughey

    1

    Embryo geometry drives formation of robust signaling gradients through receptor localization

    Zhechun Zhang, Steven Zwick, Ethan Loew, et al.



    Selected by Paul Gerald L. Sanchez and Stefano Vianello

    Symmetry breaking in the embryonic skin triggers a directional and sequential front of competence during plumage patterning

    Richard Bailleul, Carole Desmarquet-Trin Dinh, Magdalena Hidalgo, et al.



    Selected by Alexa Sadier

    A SOSEKI-based coordinate system interprets global polarity cues in Arabidopsis

    Saiko Yoshida, Alja van der Schuren, Maritza van Dop, et al.



    Selected by Martin Balcerowicz

    1

    Suppressor of Fused controls perinatal expansion and quiescence of future dentate adult neural stem cells

    Hirofumi Noguchi, Jesse Garcia Castillo, Kinichi Nakashima, et al.



    Selected by Ekaterina Dvorianinova

    The embryonic transcriptome of Arabidopsis thaliana

    Falko Hofmann, Michael A Schon, Michael D Nodine



    Selected by Chandra Shekhar Misra

    1

    The cell wall regulates dynamics and size of plasma-membrane nanodomains in Arabidopsis.

    Joseph Franics McKenna, Daniel Rolfe, Stephen E D Webb, et al.



    Selected by Marc Somssich

    Psychiatric risk gene NT5C2 regulates protein translation in human neural progenitor cells

    Rodrigo R.R. Duarte, Nathaniel D. Bachtel, Marie-Caroline Cotel, et al.



    Selected by Joanna Cross

    A Scube2-Shh feedback loop links morphogen release to morphogen signaling to enable scale invariant patterning of the ventral neural tube

    Zach Collins, Kana Ishimatsu, Tony Tsai, et al.



    Selected by Teresa Rayon

    1

    Epiblast formation by Tead-Yap-dependent expression of pluripotency factors and competitive elimination of unspecified cells

    Masakazu Hashimoto, Hiroshi Sasaki



    Selected by Sarah Bowling, Teresa Rayon

    Also in the neuroscience category:

    Single cell RNA-Seq reveals distinct stem cell populations that drive sensory hair cell regeneration in response to loss of Fgf and Notch signaling

    Mark E. Lush, Daniel C. Diaz, Nina Koenecke, et al.

    AND

    Distinct progenitor populations mediate regeneration in the zebrafish lateral line.

    Eric D Thomas, David Raible



    Selected by Rudra Nayan Das

    1

    A schizophrenia risk gene, NRGN, bidirectionally modulates synaptic plasticity via regulating the neuronal phosphoproteome

    Hongik Hwang, Matthew J Szucs, Lei J Ding, et al.



    Selected by Laura McCormick

    Actomyosin-II facilitates long-range retrograde transport of large cargoes by controlling axonal radial contractility

    Tong Wang, Wei Li, Sally Martin, et al.



    Selected by Ivana Viktorinová

    Unlimited genetic switches for cell-type specific manipulation

    Jorge Garcia-Marques, Ching-Po Yang, Isabel Espinosa-Medina, et al.



    Selected by Rafael Almeida

    1

    Defining the design requirements for an assistive powered hand exoskeleton

    Quinn A Boser, Michael R Dawson, Jonathon S Schofield, et al.



    Selected by Joanna Cross

    Strong preference for autaptic self-connectivity of neocortical PV interneurons entrains them to γ-oscillations

    Charlotte Deleuze, Gary S Bhumbra, Antonio Pazienti, et al.



    Selected by Mahesh Karnani

    Proteomic Studies reveal Disrupted in Schizophrenia 1 as a key regulator unifying neurodevelopment and synaptic function

    Adriana Ramos, Carmen Rodriguez-Seoane, Isaac Rosa, et al.



    Selected by Yasmin Lau

    Distributed correlates of visually-guided behavior across the mouse brain

    Nicholas Steinmetz, Peter Zatka-Haas, Matteo Carandini, et al.



    Selected by Craig Bertram

    Psychiatric risk gene NT5C2 regulates protein translation in human neural progenitor cells

    Rodrigo R.R. Duarte, Nathaniel D. Bachtel, Marie-Caroline Cotel, et al.



    Selected by Joanna Cross

    Single cell transcriptomics reveals spatial and temporal dynamics of gene expression in the developing mouse spinal cord

    Julien Delile, Teresa Rayon, Manuela Melchionda, et al.



    Selected by Reena Lasrado

    1

    Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing

    Qingyun Li, Zuolin Cheng, Lu Zhou, et al.



    Selected by Zheng-Shan Chong

    SABER enables highly multiplexed and amplified detection of DNA and RNA in cells and tissues

    Jocelyn Y. Kishi, Brian J. Beliveau, Sylvain W. Lapan, et al.



    Selected by Yen-Chung Chen

    LCM-seq reveals unique transcriptional adaption mechanisms of resistant neurons in spinal muscular atrophy

    Susanne Nichterwitz, Helena Storvall, Jik Nijssen, et al.

    AND

    Axon-seq decodes the motor axon transcriptome and its modulation in response to ALS

    Jik Nijssen, Julio Cesar Aguila Benitez, Rein Hoogstraaten, et al.



    Selected by Yen-Chung Chen

    Simultaneous production of diverse neuronal subtypes during early corticogenesis

    Elia Magrinelli, Robin Jan Wagener, Denis Jabaudon



    Selected by Boyan Bonev

    1

    Local protein synthesis in axon terminals and dendritic spines differentiates plasticity contexts

    Anne-Sophie Hafner, Paul Donlin-Asp, Beulah Leitch, et al.



    Selected by Dipen Rajgor

    Moving beyond P values: Everyday data analysis with estimation plots

    Joses Ho, Tayfun Tumkaya, Sameer Aryal, et al.



    Selected by Gautam Dey

    1

    Close