Synapse Formation between Central Neurons Requires Postsynaptic Expression of the MEN1 Tumor Suppressor Gene

Abstract

Synapse formation is a crucial step in the development of neuronal circuits and requires precise coordination of presynaptic and postsynaptic activities. However, molecular mechanisms that control the formation of functionally mature synaptic contacts, in particular between central neurons, remain poorly understood. To identify genes that are involved in the formation of central synapses, we made use of molluscan neurons that in culture form synaptic contacts between their somata (soma-soma synapses) in the absence of neurite outgrowth. Using single-cell mRNA differential display, we have identified a molluscan homolog of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene encoding the transcription factor menin as a gene that is upregulated during synapse formation. In vitro antisense knock-down of MEN1 mRNA blocks the formation of mature synapses between different types of identified central neurons. Moreover, immunocytochemistry and cell-specific knock-down of MEN1 mRNA show that postsynaptic but not presynaptic expression is required for synapses to form. Together, our data demonstrate that menin is a synaptogenic factor that is critically involved in a general postsynaptic mechanism of synapse formation between central neurons.