Cux1 and Cux2 Regulate Dendritic Branching, Spine Morphology, and Synapses of the Upper Layer Neurons of the Cortex

13 páginas, 8 figuras.-- PMCID: PMC2894581
Dendrite branching and spine formation determines the function of morphologically distinct and specialized neuronal subclasses. However, little is known about the programs instructing specific branching patterns in vertebrate neurons and whether such programs influence dendritic spines and synapses. Using knockout and knockdown studies combined with morphological, molecular, and electrophysiological analysis, we show that the homeobox Cux1 and Cux2 are intrinsic and complementary regulators of dendrite branching, spine development, and synapse formation in layer II-III neurons 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 remodeling genes previously implicated in cognitive defects. Accordingly, abnormal dendrites and synapses in Cux2−/− mice correlate with reduced synaptic function and defects in working memory. These demonstrate critical roles of Cux in dendritogenesis and highlight subclass-specific mechanisms of synapse regulation that contribute to the establishment of cognitive circuits.
This work was supported by MICINN grants (SAF2005-0094, SAF2008-00211, PIE-200820I166, and BFU2007-61774), a grant from Mutua Madrilen˜ a Automovilı´stica (0328-2005), and a grant from the Spanish Comunidad de Madrid CCG08-CSIC/SAL-3464. B. Cubelos holds a fellowship from the CSIC (JAEDoc2008-020), and A. Sebastian-Serrano, from the MICINN (BES-2006-13901). C.A.W. was supported by 2RO1 NS032457 from the NINDS, and J.M. Redondo, by grant SAF2006-08348. C.A.W. is an Investigator of the Howard Hughes Medical Institute. The Centro Nacional de Investigaciones Cardiovasculares is supported by the MICINN and the Pro-CNIC Foundation.