Vascular-derived SPARC and SerpinE1 regulate interneuron tangential migration and maturation
- Columbia University, United States
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
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bulk RNA-seq analysis comparing HEK293 and HBEC 5i cell linesNCBI Gene Expression Omnibus, GSE146991.
Article and author information
Author details
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.
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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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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