furrowed: Biological Overview | Evolutionary Homologs | Developmental Biology | Effects of Mutation | References

Gene name - furrowed

Synonyms -

Cytological map position - 11A2--11A7

Function - selectin - carbohydrate binding surface protein

Keywords - eye, PNS, calcium dependent protein

Symbol - fw

FlyBase ID:FBgn0001083

Genetic map position - 1-36.85

Classification - selectin

Cellular location - transmembrane

NCBI links: Precomputed BLAST | Entrez Gene

furrowed (fw) is named after a characteristic furrowing observed in the eyes of furrowed mutants. Eyes are reduced in size, especially in the ventral margin, and show many deep penetrating furrows or crevices, suggestive of an effect on the structural integrity of the retina. The furrows penetrate the entire depth of the retina, reaching the basement membrane separating the retina from the first optic lobe. The ommatidial pattern is severely disorganized and the ommatidia show altered morphology -- many lose their typical hexagonal shape. The interommatidial bristles often show altered morphology and spacing, and are occasionally duplicated. The disturbances in the patterning and morphology of ommatidia suggest that in the developing retina furrowed mutations may affect the recuitment of cells into the ommatidia. The basement membrane separating the retina from the lamina layer of the optic lobe is not clearly defined in furrowed mutants. This membrane, which provides openings for photoreceptor axons to pass, is made up of the feet of cone and pigment cells. The furrowed mutation may affect the development of these epidermal cells (Leshko-Lindsay, 1997).

Selectins, the family of proteins to which Furrowed belongs, are integral transmembrane proteins composed of three extracellular domains: an amino-terminal carbohydrate recognition or lectin domain, an epidermal growth factor (EGF)-like domain (absent in Furrowed), and a variable number of consensus repeats found in complement binding proteins, followed by a transmembrane domain and a short cytoplasmic tail at the carboxy terminus. To date, three mammalian family members have been identified that differ in the number of complement binding repeats: L-selectin has two repeats, E-selectin has six repeats and P-selectin has nine repeats. The lectin domain is homologous to the family of C-type lectins, which are calcium dependent carbohydrate binding proteins (Lesko-Lindsay, 1997 and references). The lectin domain has been demonstrated to mediate protein-carbohydrate interaction necessary for cell adhesion via recognition of complex carbohydrate determinants found in several glycoproteins and glycolipids (Varki, 1994 and Rosen, 1994). The function and role of the EGF domain and complement binding repeats seems to be (respectively), ligand recognition and protein binding (Watson, 1991 and Kansas, 1994). The cytoplasmic domain is also suspected to have a role in regulating cell adhesion by controlling cytoskeletal interactions and/or receptor avidity (Kansas, 1993).

The finding of a Drosophila selectin is the first demonstration that these proteins function outside the immune system of mammals. Another carbohydrate binding protein, Gliolectin has been characterized in Drosophila. The furrowed mutation that causes defects in patterning and in cell determination of the ommatidia and bristles is an indication that the selectin is either directly or indirectly involved in neural cell determination. The defects in morphology of the compound eye and bristles, as well as the defects in bristle polarity, indicate that FW might mediate the cell-cell adhesion interaction necessary for proper morphogenesis of these structures. This could take place by directly providing mechanical cell-cell adherence and/or directing cell-cell communication via interactions with the cytoskeleton (Leshko-Lindsay, 1997).

The Drosophila selectin Furrowed mediates intercellular planar cell polarity interactions via Frizzled stabilization

Establishment of planar cell polarity (PCP) in a tissue requires coordination of directional signals from cell to cell. It is thought that this is mediated by the core PCP factors, which include cell-adhesion molecules. This study demonstrates that furrowed, the Drosophila selectin, is required for PCP generation. Disruption of PCP in furrowed-deficient flies results from a primary defect in Fz levels and cell adhesion. Furrowed localizes at or near apical junctions, largely colocalizing with Frizzled and Flamingo (Fmi). It physically interacts with and stabilizes Frizzled, and it mediates intercellular Frizzled-Van Gogh (Vang)/Strabismus interactions, similarly to Fmi. Furrowed does so through a homophilic cell-adhesion role that is distinct from its known carbohydrate-binding function described during vertebrate blood-cell/endothelial cell interactions. Importantly, the carbohydrate function is dispensable for PCP establishment. In vivo studies suggest that Furrowed functions partially redundantly with Fmi, mediating intercellular Frizzled-Vang interactions between neighboring cells (Chin, 2013).

The data suggest that Fw serves as a homophilic cell-adhesion molecule that physically interacts with and stabilizes Fz at membranes, facilitating Fz-Vang/Stbm intercellular interactions. It was also concluded that Fw acts in a manner similar to that proposed for Fmi and thus that Fw and Fmi may act in parallel (in a partially redundant manner) to facilitate Fz-Vang interactions (Chin, 2013).

The function of Fw appears linked to that of Fz and Fmi, but the phenotypic strength of fw LOF is weaker than fz and fmi (except for the thorax). Mechanistic studies suggest that Fw is a homophilic cell-adhesion factor and physically associates with and stabilizes Fz, promoting Fz PCP function. Similarly, the cell-adhesion factor Fmi can also associate with Fz and stabilizes it at the membrane. In vivo data suggest that fw and fmi function in parallel, partially redundantly, mediating intercellular Fz-Vang interactions as intercellular 'bridges'. It is noteworthy that the double mutant phenotype of fw or fmi is not stronger than fz itself or in most cases stronger than the fmi null phenotype (except in the thorax where fw appears the more important of the two and the fmi null phenotype is not as strong as fz). In addition, Fw might affect Fz stability in a cell-adhesion-independent manner as FwΔCCP2, with no cell-adhesion capability, still stabilizes Fz when coexpressed. Thus, the data suggest that Fw performs two separate mechanistic functions in PCP: (1) Fz stabilization via association with it (this might be of different importance in distinct tissues, e.g., more important in wing discs [thorax, wing] than eye discs), and (2) cell adhesion at junctional complexes, where it stabilizes Fz to facilitate intercellular Fz- Vang interactions (a function similar to Fmi) (Chin, 2013).

Although the CCP2 domain is critical for cell adhesion, but not its Fz interaction, as Fz needs to be stabilized at cell junction complexes, the Fw effect on Fz in the absence of the CCP2 domain has no functional consequence. On both counts, Fmi is acting in a similar manner: it promotes Fz localization to subapical junctional membrane regions and overall affects Fz levels at the membrane. fw- has stronger LOF phenotypic defects in the thorax and wing, where overexpression of Fw shows no effects; in contrast, overexpression of Fw has strong effects in the eye, where LOF displays only a weak phenotype. It is likely that Fw levels are lower in the eye (hence the strong GOF PCP effect there) and Fmi largely serves the equivalent function(s) there (Chin, 2013).

In vivo and cell culture data suggest that Fw does not directly affect other core Fz-group PCP factors. The mild enhancement of Vang GOF defects is likely due to the effect of Fw on Fz, as Fz and Vang complexes antagonize each other intracellularly. Fw does not have an apparent effect on Vang levels. Thus, it appears that the phenotypic effects of Fw are mediated via its effects on Fz. Interestingly, PCP GOF effects of Fz in the eye are not only suppressed by the complete loss of fw but are 'misdirected' toward canonical Wg-signaling GOF defects, suggesting that Fw might contribute to Fz signaling specificity between the Wnt signaling branches (Chin, 2013).

Fw is the sole selectin in the Drosophila genome. In vertebrates, selectins function as cell-adhesion molecules via their carbohydrate binding C-type lectin domain, binding to glycolipids to mediate adhesion. This type of cell adhesion is prominent between leukocytes and endothelial cells, referred to as 'rolling' under flow in blood vessels. The CCP repeats are thought to serve a structural function in this context, not mediating adhesion. In the context of PCP signaling, the CCP2 domain mediates direct homophilic adhesion between Selectin/Fw in neighboring cells. This is an unexpected result and reveals a role of selectins in cell adhesion (Chin, 2013).

The adhesive behavior of Fw is however significantly weaker than bona fide structural adhesion factors required for epithelial integrity like DE-cadherin. S2 cell-based assays suggest that Fw provides about one-fifth the strength of DE-cad adhesion (determined by cell-adhesion cluster size). Accordingly, loss of function of fw does not affect epithelial integrity. In addition to this study on fw in PCP signaling, there are two additional defects associated with fw LOF alleles: (1) overgrowth in the retina (causing a 'furrowed' appearance of the eye) and (2) a mild thickening/shortening or loss of sensory bristles. Whereas the eye and bristle structure defects depend on both the CCP2 domain (cell adhesion) and the C-type lectin domain (sugar binding?), PCP establishment does not require the C-type lectin domain, suggesting that two Fw functions can be separated. As the mild overgrowth eye phenotype eye also depends on the CCP2 motif (and possibly on cell adhesion), fw could be considered a mild tissue-specific tumor suppressor. Drosophila has an open circulation system and no blood vessels, thus it is unlikely that a glycolipid binding function, as established for vertebrate selectins, is required in flies. Selectin knockouts in the mouse or zebrafish models will provide a useful approach to address whether any of the vertebrate selectins also function in PCP signaling (Chin, 2013).


There are two transcripts of 4.5 and 4.0 kb. Both transcripts are present in pupae, where they accumulate at similar levels, whereas only the larger one can be detected in wild-type adults. The genomic region proximal to the 5' end of the composite cDNA contains promoter elements needed for the start of transcription including a CAAT box and TATA box, suggesting that the 3.8 kb composite transcript should represent the full length 4.0 kb mRNA. The 4.5 kb transcript differs from the 4.0 kb RNA by the presence of additional exons in the 5' region. The 4.5 kb transcript appears to have two unique exons at the 5' end of the mRNA, suggesting that the 4.5 kb transcript is expressed from an alternative promoter. The transcription start of the alternative promoter contains a CCAAT box and TATA box (Leshko-Lindsay, 1997).

cDNA clone length - 3.8 kb

Exons - 14


Amino Acids - 978

Structural Domains

The FW protein is most similar to P-selectin, which has nine complement repeats. FW lacks the EGF-like domain found in all other selectin family members. The lectin domain, consisting of 122 amino acids, is located in the amino-terminal region. The three exons encoding the lectin are present in both transcripts. Conserved amino acids include the carbohydrate and calcium binding regions. FW lectin domain is 70% identical to the consensus lectin domain sequence. Only one Ca2+ binding site is present. The putatitive FW lectin domain is most similar to the lectin domain of selectins, since both domains have only one of the two calcium binding sites. However, the carbohydrate recognition region of the FW lectin domain (QPN) is a hybrid between the recognition sequence found in mannose-binding proteins (EPN) that is specific for mannose, and the recognition sequence found in other lectin domains that are specific for galactose (Leshko-Lindsay, 1997, citing personal communication from M Quesenberry and Y. C. Lee) There are 10 complement-like repeats, each repeat comprising 58-60 residues, immediately adjacent to one another. The seventh repeat has 86 amino acids. The ten repeats each have conserved invariant cysteines. The transmembrane domain comprises 24 highly hydrophobic resides. The cytoplasmic domain consists of 130 amino acids (Leshko-Lindsay, 1997).

furrowed: Evolutionary Homologs | Developmental Biology | Effects of Mutation | References

date revised: 18 MAR 97 

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