title: Deciphering teneurin domains that facilitate cellular recognition, cell-cell adhesion, and neurite outgrowth using atomic force microscopy-based single-cell force spectroscopy.
abstract: Teneurins are evolutionarily conserved transmembrane receptors that function as axon guidance and target selection molecules in the developing nervous system. How teneurins recognize each other, whether they establish neuronal adhesion, and which teneurin specific interactions guide neurons remains to be determined. To reveal insight into these pertinent questions we combine atomic force microscopy-based single-cell force spectroscopy with genetic engineering and quantify the interactions teneurins establish between animal cells. Using a combinatorial approach of deletions and swaps of teneurin-1 and teneurin-2 domains, we unravel that teneurins use their NHL (NCL-1, HT2A, and Lin-41) domain to select homophilic teneurins from adjacent cells. This homophilic recognition of teneurins initiates cell-cell adhesion that, dependent on the intracellular domain, strengthens over time. Neurite outgrowth assays show that establishing and strengthening of teneurin-mediated homophilic cell-cell adhesion is required to stop outgrowth. On the basis of the results, we introduce a molecular model of teneurin domains that specify cellular recognition, adhesion strengthening, and neuronal pathfinding. The combined force spectroscopy and genetic approach can be applied to quantitatively decipher the contribution of any neuronal receptor domain and more generally of a given cell surface receptor domain to cell-cell recognition and adhesion.
authors.affiliation: Novartis Research Foundation, Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
authors.forename: Jan
authors.initials: J
authors.lastname: Beckmann
authors.forename: Rajib
authors.initials: R
authors.lastname: Schubert
authors.forename: Ruth
authors.initials: R
authors.lastname: Chiquet-Ehrismann
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
mesh_terms: D001483:Base Sequence; D002448:Cell Adhesion; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D018625:Microscopy, Atomic Force / Q000379:methods*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D016501:Neurites; D060888:Real-Time Polymerase Chain Reaction; D059010:Single-Cell Analysis; D019063:Tenascin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D009419:Nerve Tissue Proteins; D019063:Tenascin; C120530:teneurin-1