Intrinsic programs regulating dendrites and synapses in the upper layer neurons of the cortex

Abstract

Dendrites and spines are key regulators of neuronal function often affected in cognitive disorders. Neuronal subclasses are characterized by a wide range of dendritic morphologies that aid their specific functions. However, how subclass-specific dendritic trees arise during vertebrate development remains largely unknown. We have recently reported that the restricted expression of Cux1 and Cux2 genes in the upper layers of the cerebral cortex determines the specific morphology of dendrites and spines and the function of these neurons. Since Cux genes are the vertebrate homologues of Drosophila Cut, which specifies the dendritic morphologies of certain sensory neuron populations, our findings suggest that mechanisms of dendrite differentiation are conserved between Drosophila and mammals, which had yet to be demonstrated. Importantly, we found that Cux genes not only modulate dendritic branching, but also dendritic spine morphogenesis, the functional synapse, and cognition. Dendritic spine stabilization was partly mediated by direct repression of genes of the Xlr family, previously implicated in cognitive defects in a model of Turner syndrome. Hence, our work indicates that neuronal subclass specific determinants may intrinsically affect synaptic activity beyond expected. The functions of Cux1 and Cux2 were additive, and complement each other to establish the final pattern of the dendritic tree and the number and strength of the synapses. This work unravels novel mechanisms of dendritogenesis and synaptogenesis and illustrates how regulating dendritic structures contributes to the specialization of upper layer neurons. It will be interesting to dissect how these mechanisms regulate cortical activity, area specialization and cognitive functions.