How adhesive interactions between cells generate and maintain animal tissue structure remains one of the most challenging and long-standing questions in cell and developmental biology. Adherens junctions (AJs) and the cadherin-catenin complexes at their core are therefore the subjects of intense research. Recent work has greatly advanced our understanding of the molecular organization of AJs and how cadherin-catenin complexes engage actin, microtubules and the endocytic machinery. As a result, we have gained important insights into the molecular mechanisms of tissue morphogenesis.

The apical transmembrane protein Crumbs is a central regulator of epithelial apical-basal polarity in Drosophila. Loss-of-function mutations in the human homologue of Crumbs, CRB1 (RP12), cause recessive retinal dystrophies, including retinitis pigmentosa. Here we show that Crumbs and CRB1 localize to corresponding subdomains of the photoreceptor apical plasma membrane: the stalk of the Drosophila photoreceptor and the inner segment of mammalian photoreceptors. These subdomains support the morphogenesis and orientation of the photosensitive membrane organelles: rhabdomeres and outer segments, respectively. Drosophila Crumbs is required to maintain zonula adherens integrity during the rapid apical membrane expansion that builds the rhabdomere. Crumbs also regulates stalk development by stabilizing the membrane-associated spectrin cytoskeleton, a function mechanistically distinct from its role in epithelial apical-basal polarity. We propose that Crumbs is a central component of a molecular scaffold that controls zonula adherens assembly and defines the stalk as an apical membrane subdomain. Defects in such scaffolds may contribute to human CRB1-related retinal dystrophies.

No abstract

No abstract

domain s Abstract The polarized architecture of epithelial cells and tissues is a fundamental determinant of animal anatomy and physiology. Recent progress made in the genetic and molecular analysis of epithelial polarity and cellular junctions in Drosophila has led to the most detailed understanding of these processes in a whole animal model system to date. Asymmetry of the plasma membrane and the differentiation of membrane domains and cellular junctions are controlled by protein complexes that assemble around transmembrane proteins such as DE-cadherin, Crumbs, and Neurexin IV, or other cytoplasmic protein complexes that associate with the plasma membrane. Much remains to be learned of how these complexes assemble, establish their polarized distribution, and contribute to the asymmetric organization of epithelial cells. CONTENTS INTRODUCTIONEpithelial tissues have emerged early during animal evolution, and their ability to form different shapes and to subdivide the body into physiologically distinct compartments is fundamental for the evolution of complex animal body plans. The plasma membrane of epithelial cells is subdivided into regions or domains that fulfill specialized roles in cell organization and physiology. The main subdivisions of the plasma membrane are the apical domain, which faces the external environment and the basolateral domain, which is in contact with the interstitial space of the body. These domains are segregated by a circumferential junctional complex (CJC) that binds adjacent epithelial cells together and forms a semipermeable barrier to the diffusion of solutes through the intercellular space (38). The movement of ions and molecules across an epithelial layer therefore requires regulated transport mechanisms that shuttle solutes from apical to basolateral, or vice versa, and allow epithelia to control the physiological composition of body compartments. In addition to the apical/basolateral distinction, membrane domains of epithelial cells are further regionalized. The basolateral membrane, for example, is subdivided into a basal domain characterized by cell-substrate adhesion and a lateral domain distinguished by cell-cell adhesion. Further, the lateral domain is partitioned into the apical CJC and a region basal to it (121).The mechanisms that establish and maintain an asymmetric distribution of lipid and protein components of the plasma membrane of epithelial cells have been intensively studied in mammalian cell culture (100). Early work in this system led to a model suggesting that the sorting of plasma membrane components in the Trans-Golgi Network (TGN) into apical and basolateral transport vesicles and the subsequent polarized delivery to the appropriate surface domain are the key mechanisms by which epithelial polarity is maintained (130). However, this model failed to explain how apical and basolateral domains are established initially, and how the two main surface domains are further regionalized. Moreover, it was recognized that apical and basolateral transport vesicles are...

Mutations within the CRB1 gene have been shown to cause human retinal diseases including retinitis pigmentosa and Leber congenital amaurosis. We have recently identified a mouse model, retinal degeneration 8 (rd8) with a single base deletion in the Crb1 gene. This mutation is predicted to cause a frame shift and premature stop codon which truncates the transmembrane and cytoplasmic domain of CRB1. Like in Drosophila crumbs (crb) mutants, staining for adherens junction proteins known to localize to the external limiting membrane, the equivalent of the zonula adherens in the mammalian retina, is discontinuous and fragmented. Shortened photoreceptor inner and outer segments are observed as early as 2 weeks after birth, suggesting a developmental defect in these structures rather than a degenerative process. Photoreceptor degeneration is observed only within regions of retinal spotting, which is seen predominantly in the inferior nasal quadrant of the eye, and is caused by retinal folds and pseudorosettes. Photoreceptor dysplasia and degeneration in Crb1 mutants strongly vary with genetic background, suggesting that the variability in phenotypes of human patients that carry mutations in CRB1 may be due to interactions with background modifiers in addition to allelic variations. The Crb1rd8 mouse model will facilitate the analysis of Crb1 function in the neural retina and the identification of interacting factors as candidate retinal disease genes.

Cadherins are involved in a variety of morphogenetic movements during animal development. However, it has been difficult to pinpoint the precise function of cadherins in morphogenetic processes due to the multifunctional nature of cadherin requirement. The data presented here indicate that homophilic adhesion promoted by Drosophila E-cadherin (DE-cadherin) mediates two cell migration events during Drosophila oogenesis. In Drosophila follicles, two groups of follicle cells, the border cells and the centripetal cells migrate on the surface of germline cells. We show that the border cells migrate as an epithelial patch in which two centrally located cells retain epithelial polarity and peripheral cells are partially depolarized. Both follicle cells and germline cells express DE-cadherin, and border cells and centripetal cells strongly upregulate the expression of DE-cadherin shortly before and during their migration. Removing DE-cadherin from either the follicle cells or the germline cells blocks migration of border cells and centripetal cells on the surface of germline cells. The function of DE-cadherin in border cells appears to be specific for migration as the formation of the border cell cluster and the adhesion between border cells are not disrupted in the absence of DE-cadherin. The speed of migration depends on the level of DE-cadherin expression, as border cells migrate more slowly when DE-cadherin activity is reduced. Finally, we show that the upregulation of DE-cadherin expression in border cells depends on the activity of the Drosophila C/EBP transcription factor that is essential for border cell migration.

Epithelial tissue formation and function requires the apical-basal polarization of individual epithelial cells. Apical polarity regulators (APRs) are an evolutionarily conserved group of key factors that govern polarity and several other aspects of epithelial differentiation. APRs compose a diverse set of molecules including a transmembrane protein (Crumbs), a serine/threonine kinase (aPKC), a lipid phosphatase (PTEN), a small GTPase (Cdc42), FERM domain proteins (Moesin, Yurt), and several adaptor or scaffolding proteins (Bazooka/Par3, Par6, Stardust, Patj). These proteins form a dynamic cooperative network that is engaged in negative-feedback regulation with basolateral polarity factors to set up the epithelial apical-basal axis. APRs support the formation of the apical junctional complex and the segregation of the junctional domain from the apical membrane. It is becoming increasingly clear that APRs interact with the cytoskeleton and vesicle trafficking machinery, regulate morphogenesis, and modulate epithelial cell growth and survival. Not surprisingly, APRs have multiple fundamental links to human diseases such as cancer and blindness.