Abstract

Cortical interneurons establish inhibitory microcircuits throughout the neocortex and their dysfunction has been implicated in epilepsy and neuropsychiatric diseases. Developmentally, interneurons migrate from a distal progenitor domain in order to populate the neocortex - a process that occurs at a slower rate in humans than in mice. In this study, we sought to identify factors that regulate the rate of interneuron maturation across the two species. Using embryonic mouse development as a model system, we found that the process of initiating interneuron migration is regulated by blood vessels of the medial ganglionic eminence (MGE), an interneuron progenitor domain. We identified two endothelial cell-derived paracrine factors, SPARC and SerpinE1, that enhance interneuron migration in mouse MGE explants and organotypic cultures. Moreover, pre-treatment of human stem cell-derived interneurons (hSC-interneurons) with SPARC and SerpinE1 prior to transplantation into neonatal mouse cortex enhanced their migration and morphological elaboration in the host cortex. Further, SPARC and SerpinE1-treated hSC-interneurons also exhibited more mature electrophysiological characteristics compared to controls. Overall, our studies suggest a critical role for CNS vasculature in regulating interneuron developmental maturation in both mice and humans.

Data availability

Bulk RNA-seq datasets for HEK293 and HBEC 5i have been uploaded to NCBI GEO under Accession Number: GSE146991

The following data sets were generated

Article and author information

Author details

  1. Matthieu Genestine

    Pathology and cell biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Daisy Ambriz

    Pathology and cell biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Gregg W Crabtree

    Pathology and cell biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Patrick Dummer

    Pathology & Cell Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Anna Molotkova

    Pathology & Cell Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Michael Quintero

    Pathology & Cell Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Angeliki Mela

    Pathology & Cell Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Saptarshi Biswas

    Pathology & Cell Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Huijuan Feng

    Systems Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Chaolin Zhang

    Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8310-7537
  11. Peter Canoll

    Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Gunnar Hargus

    Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Dritan Agalliu

    Neurology, Pathology and Cell Biology, Pharmacology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Joseph A Gogos

    Neurology, Pathology and Cell Biology, Pharmacology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Edmund Au

    Pathology and Cell Biology, Columbia University, New York, United States
    For correspondence
    ea2515@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3190-9711

Funding

Whitehall Foundation (2016-12-137)

  • Edmund Au

Irma T. Hirschl Trust

  • Edmund Au

National Institutes of Health (R03MH119443-01)

  • Edmund Au

National Institutes of Health (R01NS117695)

  • Edmund Au

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (AC-AAAZ6451) of Columbia University .

Human subjects: We obtained fetal tissue samples for research following induced termination of pregnancy for maternal indications. Sample collection followed the policies of the Columbia University Irving Medical Center Institutional Review Board. IRB waiver AAAS5541 was obtained for non-human subjects research, deemed medical waste.

Reviewing Editor

  1. Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States

Publication history

  1. Received: February 15, 2020
  2. Accepted: April 26, 2021
  3. Accepted Manuscript published: April 27, 2021 (version 1)
  4. Version of Record published: May 5, 2021 (version 2)

Copyright

© 2021, Genestine et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Matthieu Genestine
  2. Daisy Ambriz
  3. Gregg W Crabtree
  4. Patrick Dummer
  5. Anna Molotkova
  6. Michael Quintero
  7. Angeliki Mela
  8. Saptarshi Biswas
  9. Huijuan Feng
  10. Chaolin Zhang
  11. Peter Canoll
  12. Gunnar Hargus
  13. Dritan Agalliu
  14. Joseph A Gogos
  15. Edmund Au
(2021)
Vascular-derived SPARC and SerpinE1 regulate interneuron tangential migration and maturation
eLife 10:e56063.
https://doi.org/10.7554/eLife.56063

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