RESEARCH SUMMARY

Human cognition is rooted in the exact formation of stereotyped complex patterns of connectivity among an enormous diversity of neurons during cerebral cortical development. A fundamental question is to understand how the neurons of the cerebral cortex establish these precise patterns of connectivity. The cortex is organized in several functional and anatomical areas that are interconnected through stereotyped networks.

Radially, the vertebrate cortex is organized into several neuronal layers (layers I-VI), and each layer contains neurons with similar molecular identities and connectivity patterns. In general, the selective expression of transcription factors (TF) in each layer and area couples the differentiation of neuronal subtypes to the establishment of their connectivity during embryonic and early postnatal stages.

Our most recent work, using knockout and knockdown studies combined with morphological, molecular and electrophysiological analysis, demonstrates that Cux1 and Cux2 are intrinsic and complementary regulators of dendrite branching, spine development, and the functional synapse of neurons of layer II-III of the cerebral cortex.

Cux genes control the number and maturation of dendritic spines, partly through direct regulation of the expression of Xlr3b and Xlr4b, chromatin remodelling genes previously implicated in cognitive defects. We identified FAM9A, B and C as the closest orthologues of Xlr genes in humans, and found that Cux1 and 2 proteins bind to sites in FAM9A, B and C loci that are conserved between primates and humans. This indicates that it is possible that similar Cux-mediated synaptic mechanisms act in humans.

Downstream of Cux, we also found mechanisms of synaptogenesis key to cognition, including the downregulation of protein levels of NMDA receptor 2B (NMDAR2B), PSD95 and b-actin. Accordingly, abnormal dendrites and synapses in Cux2^-/- mice correlate with reduced synaptic function and defects in working memory.

Our work demonstrates critical roles for Cux in dendritogenesis and highlights novel subclass-specific mechanisms of synapse regulation that contribute to the establishment of cognitive circuits. Understanding brain wiring is an enormous task, fundamental for the dissection of normal cognitive processing and the molecular basis of disease. In particular, abnormalities in the development of layer II-III neurons are pathological, and associate to mental retardation and autism.