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L1cam-mediated developmental processes of the nervous system are differentially regulated by proteolytic processing

Cecilie Linneberg1, Christian Liebst Frisk Toft1, Kasper Kjaer-Sorensen1

  • 1Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, 8000, Aarhus C, Denmark.

Scientific Reports
|March 8, 2019
PubMed

Insights

Metalloproteinase-mediated shedding of L1 cell adhesion molecule (L1CAM) is crucial for normal brain development, particularly for efficient myelination. Specific shed fragments of L1CAM stimulate this process.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Cell Biology

Background:

  • Normal brain development requires precise regulation of cell-cell connections.
  • Mutations in L1 cell adhesion molecule (L1CAM) are linked to neurological disorders like mental retardation and hydrocephalus.
  • The shedding of L1CAM from cell surfaces is known, but its developmental role is unclear.

Purpose of the Study:

  • To investigate the role of metalloproteinase-mediated shedding of L1CAM in brain development.
  • To determine the function of L1CAM shedding during different developmental stages.
  • To identify the specific L1CAM fragments involved in its stimulatory functions.

Main Methods:

  • Utilized a zebrafish model to study L1CAM shedding.
  • Employed knockdown of zebrafish l1camb to observe developmental defects.
  • Conducted rescue experiments using proteinase-resistant and soluble L1CAM variants.

Main Results:

  • Zebrafish l1camb knockdown resulted in hydrocephalus, axonal outgrowth defects, and myelination abnormalities.
  • Proteolytic cleavage of L1CAM was not essential for axonal outgrowth or ventricular system development.
  • Metalloproteinase-mediated shedding of L1CAM is necessary for effective myelination.
  • Specific L1CAM fragments were found to mediate the stimulatory function of shed L1CAM.

Conclusions:

  • ADAM10-mediated shedding of L1CAM, regulated by its fibronectin type III domains, plays a critical role in brain development.
  • While L1CAM shedding is not essential for axonal outgrowth, it is vital for proper myelination.
  • Specific fragments of shed L1CAM possess stimulatory functions important for myelination, highlighting a novel mechanism in neural development.

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