types of cancers, bone pathologies, retinal degeneration and hypophosphatemic diseases, indicating that their activity is fundamental for tissue homeostasis. Here we review some of the debated aspects of SFRP-Wnt interactions and discuss the new and emerging roles of SFRPs. Journal of Cell Science 738 were isolated either through sequence homology with Fz receptors (Rattner et al., 1997) or, independently of Wnt activity, through their involvement in apoptosis (Melkonyan et al., 1997), or their co-purification with the heparin-binding factor hepatocyte growth factor/scattered factor (Finch et al., 1997).Since their discovery, interest in this family of molecules has grown progressively, particularly because recent observations have offered a new perspective on their functions and mechanisms of action in both development and disease. These studies indicate that SFRPs are not merely Wnt-binding proteins but can also antagonise one another's activity (Yoshino et al., 2001), bind to Fz receptors (Bafico et al., 1999;Rodriguez et al., 2005) and provide axon-guidance information (Rodriguez et al., 2005). Moreover, they can interact with other receptors or matrix molecules (Chuman et al., 2004;Hausler et al., 2004; and interfere with BMP signalling (Lee, H. et al., 2006;Muraoka et al., 2006;Yabe et al., 2003) by acting as proteinase inhibitors (Lee, H. et al., 2006). Furthermore, their expression is altered in different types of cancers (Rubin et al., 2006), in bone pathologies , retinal degeneration (Jones et al., 2000) and hypophosphatemic diseases (Berndt and Kumar, 2007), which indicates that their activity is fundamental for tissue homeostasis. Reviews that centre on Wnt antagonism by SFRPs have recently been published elsewhere (Cadigan and Liu, 2006;Jones and Jomary, 2002;Kawano and Kypta, 2003); here, we discuss new aspects of SFRP activity, and review SFRP structure, expression and interactions with Wnt proteins. The family of SFRPsThe SFRP family comprises five members in humans, SFRP1 to SFRP5, in which SFRP3 is the orthologue of the founding member Frzb. Sequence comparison and phylogenetic analysis show that SFRP1, SFRP2 and SFRP5 are closely related, and cluster together in a subgroup that diverges from the one formed by the related SFRP3 and SFRP4 (Fig. 1). This clustering also reflects a different genomic organisation. SFRP1, SFRP2 and SFRP5 are encoded by three exons on chromosome 8p12-p11.1, 4q31.3 and 10q24.1, respectively (Garcia-Hoyos et al., 2004), whereas SFRP3 and SFRP4 are both encoded by six exons -on chromosome 2q31-q33 and 7p14-p13, respectively. Orthologues of the five human genes have been found in all vertebrate species analysed so far ( Fig. 1). Notably, a third subgroup, apparently not present in mammals, has been identified in Xenopus, zebrafish and chick. The components of this subgroup, named Sizzled, Crescent and Tlc, share sequence similarities with the SFRP1-SFRP2-SFRP5 subgroup (Fig. 1), and are characterised by a very restricted and anterior expression in gastrulating embryos (B...

Summary 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 novel subclass-specific mechanisms of synapse regulation that contribute to the establishment of cognitive circuits.