Cadherin‐8 and N‐cadherin differentially regulate pre‐ and postsynaptic development of the hippocampal mossy fiber pathway

Abstract

Cells sort into regions and groups in part by their selective surface expression of particular classic cadherins during development. In the nervous system, cadherin-based sorting can define axon tracts, restrict axonal and dendritic arbors to particular regions or layers, and may encode certain aspects of synapse specificity. The underlying model has been that afferents and their targets hold in common the expression of a particular cadherin, thereby providing a recognition code of homophilic cadherin binding. However, most neurons express multiple cadherins, and it is not clear whether multiple cadherins all act similarly in shaping neural circuitry. Here we asked how two such cadherins, cadherin-8 and N-cadherin, influence the guidance and differentiation of hippocampal mossy fibers. Using organotypic hippocampal cultures, we find that cadherin-8 regulates mossy fiber fasciculation and targeting, but has little effect on CA3 dendrites. In contrast, N-cadherin regulates mossy fiber fasciculation, but has little impact on axonal growth and targeting. However, N-cadherin is essential for CA3 dendrite arborization. Both cadherins are required for formation of proper numbers of presynaptic terminals. Mechanistically, such differential actions of these two cadherins could, in theory, reflect coupling to distinct intracellular binding partners. However, we find that both cadherins bind b-catenin in dentate gyrus (DG). This suggests that cadherins may engage different intracellular signaling cascades downstream of b-catenin, coopt different extracellular binding partners, or target distinct subcellular domains. Together our findings demonstrate that cadherin-8 and N-cadherin are critical for generating the mossy fiber pathway, but that each contributes differentially to afferent and target differentiation, thereby complementing one another in the assembly of a synaptic circuit.

N-cadherin-dependent neuron–neuron interaction is required for the maintenance of activity-induced dendrite growth

“…2 A-F, J, and K). Because overexpression of members of the cadherin/catenin complex also promotes axonal outgrowth (22)(23)(24)(25)(26), a simple interpretation is that N-cadherin mediates activity-dependent neurite outgrowth by promoting extracellular contacts between axons and dendrites.…”

Cadherins and catenins in dendrite and synapse morphogenesis

“…Treatment of hippocampal slices with a peptide blocking N-cadherin prevents further dendritic elaboration and leads to dendritic retraction in CA3 neurons. 35 Expression of a construct expressing the extracellular and transmembrane domains of N-cadherin in hippocampal neurons leads to a modest increase in dendritic branching. 36 N-cadherin mediated extracellular interaction has also been implicated in activity-mediated dendritic outgrowth.…”

The classic cadherins in synaptic specificity

“…This includes the finding that overexpression of cadherin-11 increases synapse density in cultured neurons whereas overexpression of either cadherin-13, cadherin-9, or N-cadherin does not. 51,65,68 Axons of hippocampal dentate gyrus (DG) neurons grow longer on an N-cadherin substrate compared to a cadherin-8 substrate 69 and motor neurons use differential expression of type II cadherins to sort into topographically defined motor pools. 63 It was also shown that high frequency stimulation capable of inducing long term potentiation in the medial molecular layer of the hippocampus selectively decreases cadherin-8 from this layer but does not alter N-cadherin expression.…”