Matrix metalloproteinase 9/gelatinase B is required for neural crest cell migration

Efrat Monsonego-Ornan, Jenia Kosonovsky, Avi Bar, Lee Roth, Veatriki Fraggi-Rankis, Stav Simsa, Ayelet Kohl, Dalit Sela-Donenfeld*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

This study determined the role of MMP9/gelatinase B during the migration onset of Neural Crest Cells (NCC) in avian embryos. NCC are neuroepithelial progenitors that convert into mesenchyme and migrate along defined paths throughout the embryo. To engage in migration, NCC loose cell contacts, detach from the neural tube and invade the surrounding environment. Multiple signals and transcription factors that regulate these events have been identified. Nevertheless, little is known regarding effectors that act downstream to execute the actual NCC migration. Matrix metalloproteinases (MMPs) compose a large family of enzymes whose principal substrates are basement membranes, adhesion proteins and the extracellular matrix (ECM) components. A major subgroup of MMPs, the gelatinases (MMP9 and 2) are central to many adult physiological and pathological processes, such as tumor metastasis and angiogenesis, in which cell-cell and cell-matrix contacts are degraded to allow migration. As NCC undergo similar processes during development, we hypothesized that MMP9 may also promote the migration of NCC.MMP9 was found to be expressed in delaminating and migrating NCC of both cranial and trunk axial levels. Blocking MMP9 resulted in a dramatic inhibition of NCC delamination and migration, without perturbing specification or survival. This inhibition occurred at regions containing both premigratory and migrating cells, indicative for the central role of MMP9 in executing the detachment of NCC from the neural tube as well as their migration. Conversely, excess MMP9 enhanced mesenchymalization and delamination of NCC and accelerated progenitors to undergo precocious migration. Examination of the mechanistic activity of MMP9 revealed its capability to degrade the adhesion molecule N-cadherin as well as the basement-membrane protein laminin within or around NCC, respectively. Altogether, our study reveals MMP9 as a novel effector which is required for NCC delamination and migration.

Original languageAmerican English
Pages (from-to)162-177
Number of pages16
JournalDevelopmental Biology
Volume364
Issue number2
DOIs
StatePublished - 15 Apr 2012

Bibliographical note

Funding Information:
This study was supported by The Hebrew University Fund for Innovative Research and by the bilateral fund for The University of Hohenheim, Germany and The Hebrew University, Israel . We are grateful to Prof. Irit Sagi for providing MMP9 antibody and cDNA and Prof. Martin Blum for fruitful discussions.

Keywords

  • Cell migration
  • Delamination
  • ECM
  • Epithelial-to-mesenchymal transition
  • MMP
  • Neural tube

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