InteractiveFly: GeneBrief

borderless: Biological Overview | References

Gene name - borderless

Synonyms - CG16857

Cytological map position - 24E1-24E1

Function - surface transmembrane adhesion protein

Keywords - homotypic cell-cell adhesion, photoreceptor axonal tiling, optic lobe

Symbol - bdl

FlyBase ID: FBgn0028482

Genetic map position - chr2L:4324573-4331837

Classification - Immunoglobulin C-2 Type, Fibronectin type 3 domain

Cellular location - surface transmembrane

NCBI link: EntrezGene

bdl orthologs: Biolitmine

Recent literature
Cameron, S., Chen, Y. and Rao, Y. (2016). Borderless regulates glial extension and axon ensheathment. Dev Biol [Epub ahead of print]. PubMed ID: 27131624
Ensheathment of axons by glial processes is essential for normal brain function. While considerable progress has been made to define molecular and cellular mechanisms underlying the maintenance of axon ensheathment, less is known about molecular details of early events for the wrapping of axons by glial processes in the developing nervous system. This study investigated the role of the transmembrane protein Borderless (Bdl) in the developing Drosophila visual system. Bdl belongs to the immunoglobulin (Ig) superfamily, and its in vivo function is unknown. This study shows that Bdl is expressed in wrapping glia (WG) in the developing eye disc. Cell-type-specific transgene rescue and knockdown indicate that Bdl is specifically required in WG for the extension of glial processes along photoreceptor axons in the optic lobe, and axon ensheathment. These results identify Bdl as a novel glia-specific cell-surface recognition molecule in regulating glial extension and axon ensheathment.
Chen, Y., Cameron, S., Chang, W. T. and Rao, Y. (2017). Turtle interacts with borderless in regulating glial extension and axon ensheathment. Mol Brain 10(1): 17. PubMed ID: 28535795
Proper recognition between axons and glial processes is required for the establishment of axon ensheathment in the developing nervous system. Recent studies have begun to reveal molecular events underlying developmental control of axon-glia recognition. Previous work has shown that the transmembrane protein Borderless (Bdl) is specifically expressed in wrapping glia (WG), and is required for the extension of glial processes and the ensheathment of photoreceptor axons in the developing Drosophila visual system. The exact mechanism by which Bdl mediates axon-glia recognition, however, remains unknown. This study presents evidence showing that Bdl interacts with the Ig transmembrane protein Turtle (Tutl). Tutl is specifically expressed in photoreceptor axons. Loss of tutl in photoreceptors, like loss of bdl in WG, disrupts glial extension and axon ensheatment. Epistasis analysis shows that Tutl interacts genetically with Bdl. Tutl interacts with Bdl in trans in cultured cells. It is proposed that Tutl interacts with Bdl in mediating axon-glia recognition for WG extension and axon ensheathment.
Shaw, H. S., Cameron, S. A., Chang, W. T. and Rao, Y. (2019). The conserved IgSF9 protein Borderless regulates axonal transport of presynaptic components and color vision in Drosophila. J Neurosci. PubMed ID: 31235647
Normal brain function requires proper targeting of synaptic-vesicle (SV) and active-zone (AZ) components for presynaptic assembly and function. Whether and how synaptogenic signals (e.g. adhesion) at axo-dendritic contact sites promote axonal transport of presynaptic components for synapse formation, however, remain unclear. This study shows that Borderless (Bdl), a member of the conserved IgSF9-family trans-synaptic cell adhesion molecules, plays a novel and specific role in regulating axonal transport of SV components. Loss of bdl disrupts axonal transport of SV components in photoreceptor R8 axons, but does not affect the transport of mitochondria. Genetic mosaic analysis, transgene rescue and cell-type-specific knockdown indicate that Bdl is required both pre- and postsynaptically for delivering SV components in R8 axons. Consistent with a role for Bdl in R8 axons, loss of bdl causes a failure of R8-dependent phototaxis response to green light. bdl interacts genetically with imac encoding for a member of the UNC-104/Imac/KIF1A-family motor proteins, and is required for proper localization of Imac in R8 presynaptic terminals. These results support a model in which Bdl mediates specific axo-dendritic interactions in a homophilic manner, which up-regulates the Imac motor in promoting axonal transport of SV components for R8 presynaptic assembly and function.


Establishment of synaptic connections in the neuropils of the developing nervous system requires the coordination of specific neurite-neurite interactions (i.e., axon-axon, dendrite-dendrite and axon-dendrite interactions). The molecular mechanisms underlying coordination of neurite-neurite interactions for circuit assembly are incompletely understood. This study identified a novel Ig superfamily transmembrane protein that was named Borderless (Bdl), as a novel regulator of neurite-neurite interactions in Drosophila. Bdl induces homotypic cell-cell adhesion in vitro and mediates neurite-neurite interactions in the developing visual system. Bdl interacts physically and genetically with the Ig transmembrane protein Turtle, a key regulator of axonal tiling. These results also show that the receptor tyrosine phosphatase leukocyte common antigen-related protein (LAR) negatively regulates Bdl to control synaptic-layer selection. It is proposed that precise regulation of Bdl action coordinates neurite-neurite interactions for circuit formation in Drosophila (Cameron, 2013).

The presence of numerous axons and dendrites in the neuropils of the developing CNS makes it a daunting task for establishing specific synaptic connections. Studies over the last two decades have identified a number of cell-surface recognition molecules that mediate specific neurite-neurite interactions for circuit assembly. That many cell-surface recognition molecules are present broadly in developing neuropils throughout embryonic development, however, raises the question how the action of cell-surface recognition molecules is modulated temporally to ensure accuracy in circuit formation (Cameron, 2013).

The assembly of visual circuits in Drosophila is an attractive model for understanding the general mechanisms underlying spatiotemporal control of neurite-neurite interactions (Hadjieconomou, 2011; Melnattur, 2011). The Drosophila adult visual system is comprised of the compound eye and the optic lobe. The compound eye consists of ~800 ommatidia, each containing six outer photoreceptor neurons (R1-R6) for processing motion and two inner photoreceptor neurons (R7 and R8) for processing color. R1-R6 axons form synaptic connections in the superficial lamina layer, and R7 and R8 axons project through the lamina into the deeper medulla layer, where they are organized into ~800 regularly spaced columns. Each R7 and R8 axon from the same ommatidium terminate in a topographic manner in two synaptic layers within the same column. The R8 axon terminates within the M3 layer, and the R7 axon terminates in the deeper M6 layer (Cameron, 2013).

Visual circuit assembly in Drosophila involves complex neurite-neurite interactions. Specific recognition between R-cell axons and their target layers in the optic lobe have been shown to be required for synaptic-layer selection. Visual circuit assembly also requires the interactions among R-cell axons. Selection of postsynaptic targets by R1-R6 axons in the lamina requires specific axon-axon interactions. The assembly of medulla columns requires modulation of both heterotypic and homotypic axon-axon adhesion. For instance, receptor tyrosine phosphatases LAR and protein tyrosine phosphatase 69D (PTP69D) are reported to be involved in negatively regulating the adhesion between R7 and R8 axons for facilitating R7 synaptic-layer selection. And Ig-superfamily transmembrane proteins Dscam2 and Turtle (Tutl) prevent homotypic axon-axon terminal adhesion for tiling L1 and R7 axons (Ferguson, 2009), respectively. The exact mechanisms by which those cell-surface recognition molecules negatively regulate axon-axon adhesion, however, remain unknown (Cameron, 2013).

The role of a novel Ig-superfamily transmembrane protein Borderless (Bdl) in Drosophila was investigated in this study. Bdl is expressed in the developing visual system, and functions as a cell-surface recognition molecule to mediate neurite-neurite interactions. The receptor tyrosine phosphatase LAR and the Ig-superfamily transmembrane protein Tutl are key regulators of Bdl-mediated axon-axon interactions in controlling synaptic-layer selection and axonal tiling, respectively. The results shed new light on spatiotemporal control of cell-surface recognition molecules for coordinating circuit assembly (Cameron, 2013).

Tiling and self-avoidance, two cellular mechanisms discovered in the early 1980s, are important for patterning neuronal circuitry. Previous studies have identified several cell-surface recognition molecules, such as Dscam, Tutl, Protocadherins, MEGF10, and MEGF11, that mediate homotypic neurite-neurite interactions in tiling and self-avoidance. These cell-surface recognition molecules may act by mediating homotypic repulsion or de-adhesion between adjacent same-type neurites. For instance, molecular and genetic analyses of fly Dscam1 support a role for Dscam1 in mediating homotypic repulsion in dendritic self-avoidance, whereas mammalian Dscams appear to mediate de-adhesion by interfering with some unknown cell-type-specific cell adhesion molecules (Fuerst, 2009). The exact mechanisms by which these cell-surface recognition molecules mediate homotypic repulsion or de-adhesion, however, remains elusive (Cameron, 2013).

Several lines of evidence implicate Bdl as a target of Tutl in regulating R7 axonal tiling. First, overexpression of Bdl induced an R7 tiling phenotype similar to that in tutl mutants. Second, Tutl associates with Bdl in cultured cells. And third, loss of bdl rescued the tiling phenotype in tutl mutants. It is proposed that Tutl-mediated surface recognition counteracts the affinity between adjacent R7 axonal terminals by interacting with Bdl. The association of Tutl with Bdl may downregulate the level and/or adhesive activity of Bdl, thus allowing the separation of adjacent R7 axonal terminals. Since co-overexpression of Tutl and Bdl did not affect Bdl-mediated cell-cell aggregation in culture nor the Bdl-overexpression-induced tiling phenotype in flies, it is speculated that the regulation of Bdl by Tutl requires the involvement of additional regulatory molecules. Future studies are needed to determine the exact mechanism by which Tutl downregulates the function of Bdl. It will also be of interest to determine whether other cell-surface recognition molecules implicated in tiling and self-avoidance (e.g., Dscam and Protocadherins), function similarly to modulate certain cell adhesion molecules (Cameron, 2013).

The receptor tyrosine phosphatase LAR and its mammalian homologs have been shown to play important roles in axon guidance, neuronal target selection, and presynaptic development. In the developing Drosophila visual system, LAR is required for target selection of R1-R6 axons in the lamina, and synaptic-layer selection of R7 axons in the medulla. The action of LAR in R7 synaptic-layer selection reportedly involves both stabilization of axon-target interactions and down-regulation of adhesion between R7 and R8 axons. LAR-mediated axon-target interactions may involve the binding between LAR on R7 axons and an unknown ligand in the target layer, which in turn modulates the interaction between LAR and its cytoplasmic domain-binding partner Liprin to stabilize axon-target interactions. It is also reported that LAR negatively regulates an unknown cell adhesion molecule to decrease adhesion between R7 and R8 axons for facilitating synaptic-layer selection of R7 axons (Cameron, 2013).

The current results suggest strongly that LAR downregulates adhesion between R7 and R8 axons by negatively regulating Bdl. That LAR inhibited Bdl-mediated cell-cell adhesion without affecting the level of Bdl suggests that LAR inhibits adhesive activity of Bdl. Although the role of LAR in mediating axon-target interactions requires its binding to Liprin via the cytoplasmic domain, negative regulation of Bdl by LAR appears to involve a Liprin-independent mechanism. This is supported by in vitro analysis showing that a LAR mutant lacking the cytoplasmic domain also inhibited Bdl-mediated adhesion. Consistently, a previous study showed that R8-specific expression of a truncated LAR mutant lacking the cytoplasmic domain in LAR mutants could partially rescue the R7 mistargeting phenotype. LAR may directly modulate Bdl to downregulate R7-R8 adhesion, or act indirectly by interacting with other proteins. Future studies are needed to distinguish between these possibilities (Cameron, 2013).

Although negative regulation of Bdl-mediated axon-axon interactions is necessary for R7 synaptic-layer selection and tiling, it remains unclear how the presence of Bdl contributes to the formation of the R-cell axonal projection pattern in the fly visual system. Cell adhesion molecules, such as NCAM/FasII and L1-CAM/Neuroglian, have been shown to mediate selective fasciculation in axonal pathfinding. Similarly, Bdl-mediated axon-axon interactions may facilitate the projections of R7 and/or R1-R6 axons along the pioneer R8 axon. That the R-cell projection pattern remained normal in bdl mutants may be due to the presence of redundant genes. Functional redundancy among different cell adhesion molecules seems to be common in the developing nervous system, which may account for no or subtle phenotypes in mutants defective in a number of cell adhesion molecules (Cameron, 2013).

In conclusion, this study study identifies Bdl as a novel and important regulator of neurite-neurite interactions in the developing visual system. Tuning of Bdl-mediated axon-axon interactions in axonal tiling and synaptic-layer selection presents an excellent example for modulating the action of cell adhesion molecules in ensuring accuracy in circuit assembly. It is highly likely that similar mechanisms are employed for circuit assembly in mammalian nervous systems (Cameron, 2013).


Search PubMed for articles about Drosophila Borderless

Cameron, S., Chang, W. T., Chen, Y., Zhou, Y., Taran, S. and Rao, Y. (2013). Visual circuit assembly requires fine tuning of the novel Ig transmembrane protein Borderless. J Neurosci 33: 17413-17421. PubMed ID: 24174674

Ferguson, K., Long, H., Cameron, S., Chang, W. T. and Rao, Y. (2009). The conserved Ig superfamily member Turtle mediates axonal tiling in Drosophila. J Neurosci 29: 14151-14159. PubMed ID: 19906964

Fuerst, P. G., Bruce, F., Tian, M., Wei, W., Elstrott, J., Feller, M. B., Erskine, L., Singer, J. H. and Burgess, R. W. (2009). DSCAM and DSCAML1 function in self-avoidance in multiple cell types in the developing mouse retina. Neuron 64: 484-497. PubMed ID: 19945391

Hadjieconomou, D., Timofeev, K. and Salecker, I. (2011). A step-by-step guide to visual circuit assembly in Drosophila. Curr Opin Neurobiol 21: 76-84. PubMed ID: 20800474

Melnattur, K. V. and Lee, C. H. (2011). Visual circuit assembly in Drosophila. Dev Neurobiol 71: 1286-1296. PubMed ID: 21538922

date revised: 22 November 2013

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