Modifying PCDH19 levels affects cortical interneuron migration

Anna Pancho; Manuela D Mitsogiannis; Tania Aerts; Marco Dalla Vecchia; Lena K Ebert; Lieve Geenen; Lut Noterdaeme; Ria Vanlaer; Anne Stulens; Paco Hulpiau; Katrien Staes; Frans Van Roy; Peter Dedecker; Bernhard Schermer; Eve Seuntjens

doi:10.3389/fnins.2022.887478

Modifying PCDH19 levels affects cortical interneuron migration

Front Neurosci. 2022 Oct 25:16:887478. doi: 10.3389/fnins.2022.887478. eCollection 2022.

Authors

Anna Pancho¹, Manuela D Mitsogiannis¹, Tania Aerts¹, Marco Dalla Vecchia^{2

3

4}, Lena K Ebert^{5

6}, Lieve Geenen^{1

7}, Lut Noterdaeme¹, Ria Vanlaer¹, Anne Stulens¹, Paco Hulpiau^{8

9}, Katrien Staes⁸, Frans Van Roy⁸, Peter Dedecker², Bernhard Schermer^{5

6}, Eve Seuntjens¹

Affiliations

¹ Developmental Neurobiology Group, Animal Physiology and Neurobiology Division, Department of Biology, KU Leuven, Leuven, Belgium.
² Laboratory for NanoBiology, Department of Chemistry, KU Leuven, Leuven, Belgium.
³ Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
⁴ VIB Center for Inflammation Research, Ghent, Belgium.
⁵ Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁶ Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
⁷ Laboratory of Neuroplasticity and Neuroproteomics, Animal Physiology and Neurobiology Division, Department of Biology, Katholieke Universiteit Leuven, Leuven, Belgium.
⁸ Department of Biomedical Molecular Biology, Ghent University, Inflammation Research Center, VIB, Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
⁹ BioInformatics Knowledge Center (BiKC), Howest University of Applied Sciences, Bruges, Belgium.

Abstract

PCDH19 is a transmembrane protein and member of the protocadherin family. It is encoded by the X-chromosome and more than 200 mutations have been linked to the neurodevelopmental PCDH-clustering epilepsy (PCDH19-CE) syndrome. A disturbed cell-cell contact that arises when random X-inactivation creates mosaic absence of PCDH19 has been proposed to cause the syndrome. Several studies have shown roles for PCDH19 in neuronal proliferation, migration, and synapse function, yet most of them have focused on cortical and hippocampal neurons. As epilepsy can also be caused by impaired interneuron migration, we studied the role of PCDH19 in cortical interneurons during embryogenesis. We show that cortical interneuron migration is affected by altering PCDH19 dosage by means of overexpression in brain slices and medial ganglionic eminence (MGE) explants. We also detect subtle defects when PCDH19 expression was reduced in MGE explants, suggesting that the dosage of PCDH19 is important for proper interneuron migration. We confirm this finding in vivo by showing a mild reduction in interneuron migration in heterozygote, but not in homozygote PCDH19 knockout animals. In addition, we provide evidence that subdomains of PCDH19 have a different impact on cell survival and interneuron migration. Intriguingly, we also observed domain-dependent differences in migration of the non-targeted cell population in explants, demonstrating a non-cell-autonomous effect of PCDH19 dosage changes. Overall, our findings suggest new roles for the extracellular and cytoplasmic domains of PCDH19 and support that cortical interneuron migration is dependent on balanced PCDH19 dosage.

Keywords: PCDH19-CE; brain development; interneuron; medial ganglionic eminence; neurodevelopmental disorder; neuronal migration.