Connexin 43-mediated neurovascular interactions regulate neurogenesis in the adult brain subventricular zone
Nafiisha Genet,
Gael Genet,
Nicholas W. Chavkin,
Umadevi Paila,
Jennifer S. Fang,
Hema H. Vasavada,
Joshua S. Goldberg,
Bipul R. Acharya,
Neha S. Bhatt,
Kasey Baker,
Stephanie P. McDonnell,
Mahalia Huba,
Danya Sankaranarayanan,
Gerry Z.M. Ma,
Anne Eichmann,
Jean-Leon Thomas,
Charles ffrench-Constant,
Karen K. Hirschi
Affiliations
Nafiisha Genet
Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA; Corresponding author
Gael Genet
Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
Nicholas W. Chavkin
Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
Umadevi Paila
Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
Jennifer S. Fang
Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
Hema H. Vasavada
Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
Joshua S. Goldberg
Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
Bipul R. Acharya
Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
Neha S. Bhatt
Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06511, USA
Kasey Baker
Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06511, USA; Departments of Neuroscience and Cell Biology, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
Stephanie P. McDonnell
Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
Mahalia Huba
Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
Danya Sankaranarayanan
Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
Gerry Z.M. Ma
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK; Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK
Anne Eichmann
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
Jean-Leon Thomas
Departments of Neuroscience and Cell Biology, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
Charles ffrench-Constant
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK; Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK
Karen K. Hirschi
Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA; Corresponding author
Summary: The subventricular zone (SVZ) is the largest neural stem cell (NSC) niche in the adult brain; herein, the blood-brain barrier is leaky, allowing direct interactions between NSCs and endothelial cells (ECs). Mechanisms by which direct NSC-EC interactions in the adult SVZ control NSC behavior are unclear. We found that Cx43 is highly expressed by SVZ NSCs and ECs, and its deletion in either leads to increased NSC proliferation and neuroblast generation, suggesting that Cx43-mediated NSC-EC interactions maintain NSC quiescence. This is further supported by single-cell RNA sequencing and in vitro studies showing that ECs control NSC proliferation by regulating expression of genes associated with NSC quiescence and/or activation in a Cx43-dependent manner. Cx43 mediates these effects in a channel-independent manner involving its cytoplasmic tail and ERK activation. Such insights inform adult NSC regulation and maintenance aimed at stem cell therapies for neurodegenerative disorders.
