Structural Requirements for Outside-In and Inside-Out Signaling by <i>Drosophila</i> Neuroglian, a Member of the L1 Family of Cell Adhesion Molecules

Hortsch, Michael; Homer, D. S.; Malhotra, Jyoti; Chang, Sehyun; Frankel, J.; Jefford, Gregory; Dubreuil, Ronald R.

doi:10.1083/jcb.142.1.251

Cited by 67 publications

(70 citation statements)

References 35 publications

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“…The Fas2 tumor invasion and blocked BC migration phenotypes indicate that Fas2 is both necessary and sufficient to inhibit invasion, and that its pattern of expression predicts epithelial invasion. (Goodman et al, 1997); Dlg-4.1 (Lue et al, 1996); Nrg-Ank (Hortsch et al, 1998); 4.1-Spec/Act and Ank-Spec/Act (Bennett and Baines, 2001). Scrib, which is also localized to BLJ, is not shown since we found that its loss does not cause invasion as defined in this work.…”

Section: Spatio-temporal Expression Of Fas2 Predicts Epithelial Invassupporting

confidence: 41%

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Basolateral junctions are sufficient to suppress epithelial invasion during Drosophila oogenesis

Szafrański

Goode

2006

Developmental Dynamics

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Epithelial junctions play crucial roles during metazoan evolution and development by facilitating tissue formation, maintenance, and function. Little is known about the role of distinct types of junctions in controlling epithelial transformations leading to invasion of neighboring tissues. Discovering the key junction complexes that control these processes and how they function may also provide mechanistic insight into carcinoma cell invasion. Here, using the Drosophila ovary as a model, we show that four proteins of the basolateral junction (BLJ), Fasciclin-2, Neuroglian, Discs-large, and Lethal-giant-larvae, but not proteins of other epithelial junctions, directly suppress epithelial tumorigenesis and invasion. Remarkably, the expression pattern of Fasciclin-2 predicts which cells will invade. We compared the apicobasal polarity of BLJ tumor cells to border cells (BCs), an epithelium-derived cluster that normally migrates during mid-oogenesis. Both tumor cells and BCs differentiate a lateralized membrane pattern that is necessary but not sufficient for invasion. Independent of lateralization, derepression of motility pathways is also necessary, as indicated by a strong linear correlation between faster BC migration and an increased incidence of tumor invasion. However, without membrane lateralization, derepression of motility pathways is also not sufficient for invasion. Our results demonstrate that spatiotemporal patterns of basolateral junction activity directly suppress epithelial invasion by organizing the cooperative activity of distinct polarity and motility pathways. Developmental Dynamics 236:364 -373, 2007.

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Section: Spatio-temporal Expression Of Fas2 Predicts Epithelial Invassupporting

confidence: 41%

“…Second, Fas2 directly binds Dlg (Goodman et al, 1997). Third, molecular interactions between Nrg, Ankyrin, and Spectrin (Dubreuil et al, 1996;Hortsch et al, 1998) suggest a manner for Nrg to be linked to Fas2-Dlg through membrane protein 4.1 (Fig. 1B).…”

Section: Fas2 Dlg Lgl and Nrg Function Together To Suppress Invasionmentioning

confidence: 99%

Basolateral junctions are sufficient to suppress epithelial invasion during Drosophila oogenesis

Szafrański

Goode

2006

Developmental Dynamics

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“…The Schneider-2 (S2) cell line, which can express transfected genes, has revealed molecular mechanisms of cell adhesion [Hortsch and Bieber, 1991], much as Xenopus oocytes have done for ion channel function. Drosophila Neuroglian, whose human counterpart, L1 cell adhesion molecule (L1CAM/Nrg), is defective in a complex set of MR disorders [Weller and Gartner, 2001], controls axon pathfinding by regulating adhesive interactions between neurons [Hall and Bieber, 1997;Hortsch et al, 1998]. S2 cells expressing mutant forms of Neuroglian could be used to screen for drugs that restore cell adhesion.…”

Section: Prospects For Drug Discovery and Developmentmentioning

confidence: 99%

Mental retardation genes in drosophila: New approaches to understanding and treating developmental brain disorders

Restifo

2005

Ment. Retard. Dev. Disabil. Res. Rev.

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Drosophila melanogaster is emerging as a valuable genetic model system for the study of mental retardation (MR). MR genes are remarkably similar between humans and fruit flies. Cognitive behavioral assays can detect reductions in learning and memory in flies with mutations in MR genes. Neuroanatomical methods, including some at single-neuron resolution, are helping to reveal the cellular bases of faulty brain development caused by MR gene mutations. Drosophila fragile X mental retardation 1 (dfmr1) is the fly counterpart of the human gene whose malfunction causes fragile X syndrome. Research on the fly gene is leading the field in molecular mechanisms of the gene product's biological function and in pharmacological rescue of brain and behavioral phenotypes. Future work holds the promise of using genetic pathway analysis and primary neuronal culture methods in Drosophila as tools for drug discovery for a wide range of MR and related disorders.

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“…These results suggested that sodium channel ␤ subunits function as CAMs. CAMs of the L1 family also bind directly to cytoskeletal elements such as ankyrin (12,13,(15)(16)(17). Sodium channels have been shown to colocalize with ankyrin G and spectrin at axon initial segments and nodes of Ranvier, and there is some evidence to show that sodium channels bind ankyrin directly in vitro (18 -22).…”

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confidence: 99%

“…Ankyrins associate via their membrane binding domains with several ion channels and cell adhesion molecules of the L1 family (12)(13)(14)(15)(16)(17). The membrane binding domain of ankyrin contains four subdomains that are each composed of six ankyrin repeats (24).…”

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confidence: 99%

Sodium Channel β Subunits Mediate Homophilic Cell Adhesion and Recruit Ankyrin to Points of Cell-Cell Contact

Malhotra¹,

Kazen-Gillespie²,

Hortsch³

et al. 2000

Journal of Biological Chemistry

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259

281

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Sodium channels isolated from mammalian brain are composed of ␣, ␤1, and ␤2 subunits. The auxiliary ␤ subunits do not form the ion conducting pore, yet play important roles in channel modulation and plasma membrane expression. ␤1 and ␤2 are transmembrane proteins with one extracellular V-set immunoglobulin (Ig) protein domain. It has been shown recently that ␤1 and ␤2 interact with the extracellular matrix proteins tenascin-C and tenascin-R. In the present study we show that rat brain ␤1 and ␤2, but not ␣IIA, subunits interact in a trans-homophilic fashion, resulting in recruitment of the cytoskeletal protein ankyrin to sites of cell-cell contact in transfected Drosophila S2 cells. Whereas ␣IIA subunits expressed alone do not cause cellular aggregation, ␤ subunits co-expressed with ␣IIA retain the ability to adhere and recruit ankyrin. Truncated ␤ subunits lacking cytoplasmic domains interact homophilically to produce cell aggregation but do not recruit ankyrin. Thus, the cytoplasmic domains of ␤1 and ␤2 are required for cytoskeletal interactions. It is hypothesized that sodium channel ␤ subunits serve as a critical communication link between the extracellular and intracellular environments of the neuron and may play a role in sodium channel placement at nodes of Ranvier.Control of the cell surface density and localization of voltagegated sodium channels are critical aspects of neuronal function. This is especially important at nodes of Ranvier of myelinated axons where high densities of sodium channels are needed for rapid and reliable saltatory conduction (1, 2). Sodium channels from mammalian brain are heterotrimeric structures composed of a central pore forming ␣ subunit and two auxiliary subunits, ␤1 and ␤2 (3, 4). Though the ␤ subunits do not form the ion conducting pore, they play critical roles in channel gating, voltage dependence of activation and inactivation, and channel plasma membrane expression levels (5-8). ␤1 and ␤2 contain Ig-like extracellular domains and are members of the V-set of the Ig superfamily, which includes many cell adhesion molecules (CAMs) 1 (9). ␤1 and ␤2 have recently been shown to interact with the extracellular matrix proteins tenascin-C and tenascin-R (10, 11). Transfected cells expressing ␤1 or ␤2 subunits initially bind to and then are repelled from a tenascin-R substrate (11). Purified sodium channels or the bacterially expressed ␤2 subunit extracellular domain bind tenascin-C and tenascin-R in an enzyme-linked immunosorbent type biochemical assay (10). These results suggested that sodium channel ␤ subunits function as CAMs. CAMs of the L1 family also bind directly to cytoskeletal elements such as ankyrin (12,13,(15)(16)(17). Sodium channels have been shown to colocalize with ankyrin G and spectrin at axon initial segments and nodes of Ranvier, and there is some evidence to show that sodium channels bind ankyrin directly in vitro (18 -22). However, it is not known to which sodium channel subunit ankyrin binds. Because ␤1 and ␤2 are structurally and functionally homologous ...

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Structural Requirements for Outside-In and Inside-Out Signaling by Drosophila Neuroglian, a Member of the L1 Family of Cell Adhesion Molecules

Cited by 67 publications

References 35 publications

Basolateral junctions are sufficient to suppress epithelial invasion during Drosophila oogenesis

Basolateral junctions are sufficient to suppress epithelial invasion during Drosophila oogenesis

Mental retardation genes in drosophila: New approaches to understanding and treating developmental brain disorders

Sodium Channel β Subunits Mediate Homophilic Cell Adhesion and Recruit Ankyrin to Points of Cell-Cell Contact

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