The role of the neural cell adhesion molecule L1 and its ligands in normal brain development and hereditary brain diseases

• Research unit: EU RFP
• Project number: 96.0310

Key words (English)

Neural cell adhesion molecules; L1; axon growth;
CAM interactions

Alternative project number (English)

EU project number: BIO4CT96-0450

Research programs (English)

EU-programme: 4. Frame Research Programme - 4.1 Biotechnology

Short description (English)

See abstract

Partners and International Organizations (English)

E.M. Bock, Kopenhagen (DK), F. Jimenez, Madrid (E), S.J Kenwrick, Cambridge (UK), F.G. Rathjen, Berlin (D), F.S. Walsh, London (UK), H.Lundsbeck Kopenhagen (DK)

Abstract (English)

The neural cell adhesion molecule axonin-1/TAG-1 plays a role in axon growth and guidance. We have determined the crystal structure of the ligand-binding fragment of axonin-1 comprising the first four immunoglobulin (Ig) domains. Axonin-1Ig1-4 is U-shaped due to contacts between domains 1 and 4 and domains 2 and 3. In the crystals, these molecules form a string with adjacent molecules oriented in an antiparallel fashion and their C-termini perpendicular to the string. This suggests that cell adhesion by homophilic axonin-1 interaction occurs by the formation of a linear zipper in which the axonin-1 molecules are alternately provided by the two apposed membranes. In accordance with this model, mutations in a loop critical for the formation of the zipper resulted in the loss of the homophilic binding capa-city of axonin-1.
An interaction of growth cone axonin-1 with floor-plate NrCAM was shown to play a crucial role in commissural axon guidance across the midline of the spinal cord. We found that axonin-1 mediates a guidance signal without promoting axon elongation. In an in vitro assay, commissural axons grew preferentially on stripes coated with a mixture of NrCAM and NgCAM. This preference was abolished in the presence of anti-axonin-1 antibodies without a decrease in neurite length. Likewise, commissural axons in vivo only fail to extend along the longitudinal axis when both NrCAM and NgCAM interactions, but not when axonin-1 and NrCAM or axonin-1 and NgCAM interactions are perturbed. Thus, axonin-1 is involved in guidance of commissural axons without promoting their growth.

References in databases (English)

Swiss Database: Euro-DB of the
State Secretariat for Education and Research
Hallwylstrasse 4
CH-3003 Berne, Switzerland
Tel. [phone]
Swiss Project-Number: 96.0310