A genome-wide functional screen shows MAGI-1 is an L1CAM-dependent stabilizer of apical junctions in C. elegans

Allison Lynch, Theresa Grana, Elisabeth Cox, Annabelle Couthier, Michel Cameron, Ian Chin-Sang, Jonathan Pettitt, Jeff Hardin

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background
In multicellular organisms, cell-cell junctions are involved in many aspects of tissue morphogenesis. Alpha-catenin links the cadherin-catenin complex (CCC) to the actin cytoskeleton, stabilizing cadherin-dependent adhesions.

Results
To identify modulators of cadherin-based cell adhesion, we conducted a genome-wide RNAi screen in C. elegans and uncovered MAGI-1, a highly conserved protein scaffold. Loss of magi-1 function in wild-type embryos results in disorganized epithelial migration and occasional morphogenetic failure. MAGI-1 physically interacts with the putative actin regulator AFD- 1/afadin; knocking down magi-1 or afd-1 function in a hypomorphic ¿-catenin background leads to complete morphogenetic failure and actin disorganization in the embryonic epidermis. MAGI- 1 and AFD-1 localize to a unique domain in the apical junction and normal accumulation of MAGI-1 at junctions requires SAX-7/L1CAM, which can bind MAGI-1 via its C-terminus. Depletion of MAGI-1 leads to loss of spatial segregation and expansion of apical junctional domains and greater mobility of junctional proteins.

Conclusions
Our screen is the first genome-wide approach to identify proteins that function synergistically with the CCC during epidermal morphogenesis in a living embryo. We demonstrate novel physical interactions between MAGI-1, AFD-1/afadin and SAX-7/L1CAM, which are part of a functional interactome that includes components of the core CCC. Our results further suggest MAGI-1 helps to partition and maintain a stable, spatially ordered apical junction during morphogenesis.

Original languageEnglish
Pages (from-to)1891–1899
Number of pages9
JournalCurrent Biology
Volume22
Issue number20
DOIs
Publication statusPublished - 23 Oct 2012

Fingerprint

Neural Cell Adhesion Molecule L1
cadherins
Cadherins
Catenins
Genes
Genome
Morphogenesis
genome
morphogenesis
Actins
actin
Embryonic Structures
alpha Catenin
scaffolding proteins
intercellular junctions
Proteins
Intercellular Junctions
Cell adhesion
RNA Interference
microfilaments

Cite this

Lynch, A., Grana, T., Cox, E., Couthier, A., Cameron, M., Chin-Sang, I., ... Hardin, J. (2012). A genome-wide functional screen shows MAGI-1 is an L1CAM-dependent stabilizer of apical junctions in C. elegans. Current Biology, 22(20), 1891–1899. https://doi.org/10.1016/j.cub.2012.08.024

A genome-wide functional screen shows MAGI-1 is an L1CAM-dependent stabilizer of apical junctions in C. elegans. / Lynch, Allison; Grana, Theresa; Cox, Elisabeth; Couthier, Annabelle; Cameron, Michel; Chin-Sang, Ian; Pettitt, Jonathan; Hardin, Jeff.

In: Current Biology, Vol. 22, No. 20, 23.10.2012, p. 1891–1899.

Research output: Contribution to journalArticle

Lynch, A, Grana, T, Cox, E, Couthier, A, Cameron, M, Chin-Sang, I, Pettitt, J & Hardin, J 2012, 'A genome-wide functional screen shows MAGI-1 is an L1CAM-dependent stabilizer of apical junctions in C. elegans', Current Biology, vol. 22, no. 20, pp. 1891–1899. https://doi.org/10.1016/j.cub.2012.08.024
Lynch, Allison ; Grana, Theresa ; Cox, Elisabeth ; Couthier, Annabelle ; Cameron, Michel ; Chin-Sang, Ian ; Pettitt, Jonathan ; Hardin, Jeff. / A genome-wide functional screen shows MAGI-1 is an L1CAM-dependent stabilizer of apical junctions in C. elegans. In: Current Biology. 2012 ; Vol. 22, No. 20. pp. 1891–1899.
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abstract = "Background In multicellular organisms, cell-cell junctions are involved in many aspects of tissue morphogenesis. Alpha-catenin links the cadherin-catenin complex (CCC) to the actin cytoskeleton, stabilizing cadherin-dependent adhesions. Results To identify modulators of cadherin-based cell adhesion, we conducted a genome-wide RNAi screen in C. elegans and uncovered MAGI-1, a highly conserved protein scaffold. Loss of magi-1 function in wild-type embryos results in disorganized epithelial migration and occasional morphogenetic failure. MAGI-1 physically interacts with the putative actin regulator AFD- 1/afadin; knocking down magi-1 or afd-1 function in a hypomorphic ¿-catenin background leads to complete morphogenetic failure and actin disorganization in the embryonic epidermis. MAGI- 1 and AFD-1 localize to a unique domain in the apical junction and normal accumulation of MAGI-1 at junctions requires SAX-7/L1CAM, which can bind MAGI-1 via its C-terminus. Depletion of MAGI-1 leads to loss of spatial segregation and expansion of apical junctional domains and greater mobility of junctional proteins. Conclusions Our screen is the first genome-wide approach to identify proteins that function synergistically with the CCC during epidermal morphogenesis in a living embryo. We demonstrate novel physical interactions between MAGI-1, AFD-1/afadin and SAX-7/L1CAM, which are part of a functional interactome that includes components of the core CCC. Our results further suggest MAGI-1 helps to partition and maintain a stable, spatially ordered apical junction during morphogenesis.",
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AU - Cameron, Michel

AU - Chin-Sang, Ian

AU - Pettitt, Jonathan

AU - Hardin, Jeff

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AB - Background In multicellular organisms, cell-cell junctions are involved in many aspects of tissue morphogenesis. Alpha-catenin links the cadherin-catenin complex (CCC) to the actin cytoskeleton, stabilizing cadherin-dependent adhesions. Results To identify modulators of cadherin-based cell adhesion, we conducted a genome-wide RNAi screen in C. elegans and uncovered MAGI-1, a highly conserved protein scaffold. Loss of magi-1 function in wild-type embryos results in disorganized epithelial migration and occasional morphogenetic failure. MAGI-1 physically interacts with the putative actin regulator AFD- 1/afadin; knocking down magi-1 or afd-1 function in a hypomorphic ¿-catenin background leads to complete morphogenetic failure and actin disorganization in the embryonic epidermis. MAGI- 1 and AFD-1 localize to a unique domain in the apical junction and normal accumulation of MAGI-1 at junctions requires SAX-7/L1CAM, which can bind MAGI-1 via its C-terminus. Depletion of MAGI-1 leads to loss of spatial segregation and expansion of apical junctional domains and greater mobility of junctional proteins. Conclusions Our screen is the first genome-wide approach to identify proteins that function synergistically with the CCC during epidermal morphogenesis in a living embryo. We demonstrate novel physical interactions between MAGI-1, AFD-1/afadin and SAX-7/L1CAM, which are part of a functional interactome that includes components of the core CCC. Our results further suggest MAGI-1 helps to partition and maintain a stable, spatially ordered apical junction during morphogenesis.

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