Amelioration of the abnormal phenotype of a new L1 syndrome mouse mutation with L1 mimetics.
FASEB j.. 2021-01-23; 35(2):
DOI: 10.1096/fj.202002163r
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Loers G(1), Appel D(2), Lutz D(1), Congiu L(1), Kleene R(1), Hermans-Borgmeyer
I(1), Schäfer MKE(2)(3)(4), Schachner M(1)(5).
Author information:
(1)Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf,
Hamburg, Germany.
(2)Department of Anesthesiology, University Medical Center of the Johannes
Gutenberg-University Mainz, Mainz, Germany.
(3)Focus Program Translational Neurosciences, Johannes Gutenberg-University of
Mainz, Mainz, Germany.
(4)Research Centre for Immunotherapy, Johannes Gutenberg-University of Mainz,
Mainz, Germany.
(5)Department of Cell Biology and Neuroscience, Keck Center for Collaborative
Neuroscience, Rutgers University, Piscataway, NJ, USA.
L1 syndrome is a rare developmental disorder characterized by hydrocephalus of
varying severity, intellectual deficits, spasticity of the legs, and adducted
thumbs. Therapy is limited to symptomatic relief. Numerous gene mutations in the
L1 cell adhesion molecule (L1CAM, hereafter abbreviated L1) were identified in
L1 syndrome patients, and those affecting the extracellular domain of this
transmembrane type 1 glycoprotein show the most severe phenotypes. Previously
analyzed rodent models of the L1 syndrome focused on L1-deficient animals or
mouse mutants with abrogated cell surface expression of L1, making it difficult
to test L1 function-triggering mimetic compounds with potential therapeutic
value. To overcome this impasse, we generated a novel L1 syndrome mouse with a
mutation of aspartic acid at position 201 in the extracellular part of L1
(p.D201N, hereafter termed L1-201) that displays a cell surface-exposed L1
accessible to the L1 mimetics. Behavioral assessment revealed an increased
neurological deficit score and increased locomotor activity in male L1-201 mice
carrying the mutation on the X-chromosome. Histological analyses of L1-201 mice
showed features of the L1 syndrome, including enlarged ventricles and reduced
size of the corpus callosum. Expression levels of L1-201 protein as well as
extent of cell surface biotinylation and immunofluorescence labelling of
cultured cerebellar neurons were normal. Importantly, treatment of these
cultures with the L1 mimetic compounds duloxetine, crotamiton, and trimebutine
rescued impaired cell migration and survival as well as neuritogenesis.
Altogether, the novel L1 syndrome mouse model provides a first experimental
proof-of-principle for the potential therapeutic value of L1 mimetic compounds.
© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on
behalf of Federation of American Societies for Experimental Biology.