Mapping combinatorial expression of non-clustered protocadherins in the developing brain identifies novel PCDH19-mediated cell adhesion properties

Stefka Mincheva-Tasheva, Chandran Pfitzner, Raman Kumar, Idha Kurtsdotter, Michaela Scherer, Tarin Ritchie, Jonas Muhr, Jozef Gecz, Paul Q. Thomas

Research output: Contribution to journalArticlepeer-review

Abstract

Non-clustered protocadherins (ncPcdhs) are adhesive molecules with spatio-temporally regulated overlapping expression in the developing nervous system. Although their unique role in neurogenesis has been widely studied, their combinatorial role in brain physiology and pathology is poorly understood. Using probabilistic cell typing by in situ sequencing, we demonstrate combinatorial inter- and intra-familial expression of ncPcdhs in the developing mouse cortex and hippocampus, at single-cell resolution. We discovered the combinatorial expression of Protocadherin-19 (Pcdh19), a protein involved in PCDH19-clustering epilepsy, with Pcdh1, Pcdh9 or Cadherin 13 (Cdh13) in excitatory neurons. Using aggregation assays, we demonstrate a code-specific adhesion function of PCDH19; mosaic PCDH19 absence in PCDH19+9 and PCDH19 + CDH13, but not in PCDH19+1 codes, alters cell–cell interaction. Interestingly, we found that PCDH19 as a dominant protein in two heterophilic adhesion codes could promote trans-interaction between them. In addition, we discovered increased CDH13-mediated cell adhesion in the presence of PCDH19, suggesting a potential role of PCDH19 as an adhesion mediator of CDH13. Finally, we demonstrated novel cis-interactions between PCDH19 and PCDH1, PCDH9 and CDH13. These observations suggest that there is a unique combinatorial code with a cell- and region-specific characteristic where a single molecule defines the heterophilic cell–cell adhesion properties of each code.

Original languageEnglish
Article number230383
JournalOpen Biology
Volume14
Issue number4
DOIs
Publication statusPublished or Issued - 17 Apr 2024

Keywords

  • brain development
  • cell adhesion
  • non-clustered protocadherins
  • PCDH19-clustering epilepsy
  • Protocadherin 19

ASJC Scopus subject areas

  • General Neuroscience
  • Immunology
  • General Biochemistry,Genetics and Molecular Biology

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