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A Sensitized Screen for Genes Promoting Invadopodia Function In Vivo: CDC-42 and Rab GDI-1 Direct Distinct Aspects of Invadopodia Formation.

Publication ,  Journal Article
Lohmer, LL; Clay, MR; Naegeli, KM; Chi, Q; Ziel, JW; Hagedorn, EJ; Park, JE; Jayadev, R; Sherwood, DR
Published in: PLoS genetics
January 2016

Invadopodia are specialized membrane protrusions composed of F-actin, actin regulators, signaling proteins, and a dynamically trafficked invadopodial membrane that drive cell invasion through basement membrane (BM) barriers in development and cancer. Due to the challenges of studying invasion in vivo, mechanisms controlling invadopodia formation in their native environments remain poorly understood. We performed a sensitized genome-wide RNAi screen and identified 13 potential regulators of invadopodia during anchor cell (AC) invasion into the vulval epithelium in C. elegans. Confirming the specificity of this screen, we identified the Rho GTPase cdc-42, which mediates invadopodia formation in many cancer cell lines. Using live-cell imaging, we show that CDC-42 localizes to the AC-BM interface and is activated by an unidentified vulval signal(s) that induces invasion. CDC-42 is required for the invasive membrane localization of WSP-1 (N-WASP), a CDC-42 effector that promotes polymerization of F-actin. Loss of CDC-42 or WSP-1 resulted in fewer invadopodia and delayed BM breaching. We also characterized a novel invadopodia regulator, gdi-1 (Rab GDP dissociation inhibitor), which mediates membrane trafficking. We show that GDI-1 functions in the AC to promote invadopodia formation. In the absence of GDI-1, the specialized invadopodial membrane was no longer trafficked normally to the invasive membrane, and instead was distributed to plasma membrane throughout the cell. Surprisingly, the pro-invasive signal(s) from the vulval cells also controls GDI-1 activity and invadopodial membrane trafficking. These studies represent the first in vivo screen for genes regulating invadopodia and demonstrate that invadopodia formation requires the integration of distinct cellular processes that are coordinated by an extracellular cue.

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Published In

PLoS genetics

DOI

EISSN

1553-7404

ISSN

1553-7390

Publication Date

January 2016

Volume

12

Issue

1

Start / End Page

e1005786

Related Subject Headings

  • Signal Transduction
  • Podosomes
  • Neoplasms
  • Humans
  • Guanine Nucleotide Dissociation Inhibitors
  • Gene Expression Regulation, Developmental
  • GTP-Binding Proteins
  • Extracellular Matrix
  • Disease Models, Animal
  • Developmental Biology
 

Citation

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Lohmer, L. L., Clay, M. R., Naegeli, K. M., Chi, Q., Ziel, J. W., Hagedorn, E. J., … Sherwood, D. R. (2016). A Sensitized Screen for Genes Promoting Invadopodia Function In Vivo: CDC-42 and Rab GDI-1 Direct Distinct Aspects of Invadopodia Formation. PLoS Genetics, 12(1), e1005786. https://doi.org/10.1371/journal.pgen.1005786
Lohmer, Lauren L., Matthew R. Clay, Kaleb M. Naegeli, Qiuyi Chi, Joshua W. Ziel, Elliott J. Hagedorn, Jieun E. Park, Ranjay Jayadev, and David R. Sherwood. “A Sensitized Screen for Genes Promoting Invadopodia Function In Vivo: CDC-42 and Rab GDI-1 Direct Distinct Aspects of Invadopodia Formation.PLoS Genetics 12, no. 1 (January 2016): e1005786. https://doi.org/10.1371/journal.pgen.1005786.
Lohmer LL, Clay MR, Naegeli KM, Chi Q, Ziel JW, Hagedorn EJ, et al. A Sensitized Screen for Genes Promoting Invadopodia Function In Vivo: CDC-42 and Rab GDI-1 Direct Distinct Aspects of Invadopodia Formation. PLoS genetics. 2016 Jan;12(1):e1005786.
Lohmer, Lauren L., et al. “A Sensitized Screen for Genes Promoting Invadopodia Function In Vivo: CDC-42 and Rab GDI-1 Direct Distinct Aspects of Invadopodia Formation.PLoS Genetics, vol. 12, no. 1, Jan. 2016, p. e1005786. Epmc, doi:10.1371/journal.pgen.1005786.
Lohmer LL, Clay MR, Naegeli KM, Chi Q, Ziel JW, Hagedorn EJ, Park JE, Jayadev R, Sherwood DR. A Sensitized Screen for Genes Promoting Invadopodia Function In Vivo: CDC-42 and Rab GDI-1 Direct Distinct Aspects of Invadopodia Formation. PLoS genetics. 2016 Jan;12(1):e1005786.

Published In

PLoS genetics

DOI

EISSN

1553-7404

ISSN

1553-7390

Publication Date

January 2016

Volume

12

Issue

1

Start / End Page

e1005786

Related Subject Headings

  • Signal Transduction
  • Podosomes
  • Neoplasms
  • Humans
  • Guanine Nucleotide Dissociation Inhibitors
  • Gene Expression Regulation, Developmental
  • GTP-Binding Proteins
  • Extracellular Matrix
  • Disease Models, Animal
  • Developmental Biology