Deciphering Teneurin Domains That Facilitate Cellular
Recognition, Cell–Cell Adhesion, and Neurite Outgrowth Using
Atomic Force Microscopy-Based Single-Cell Force Spectroscopy
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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