Role of the cytoplasmic domain of the L1 cell adhesion molecule in brain development.

Mutations in the human L1CAM gene cause X-linked hydrocephalus and MASA (Mental retardation, Aphasia, Shuffling gait, Adducted thumbs) syndrome. In vitro studies have shown that the L1 cytoplasmic domain (L1CD) is involved in L1 trafficking, neurite branching, signaling, and interactions with the cytoskeleton. L1cam knockout (L1(KO)) mice have hydrocephalus, a small cerebellum, hyperfasciculation of corticothalamic tracts, and abnormal peripheral nerves. To explore the function of the L1CD, we made three new mice lines in which different parts of the L1CD have been altered. In all mutant lines L1 protein is expressed and transported into the axon. Interestingly, these new L1CD mutant lines display normal brain morphology. However, the expression of L1 protein in the adult is dramatically reduced in the two L1CD mutant lines that lack the ankyrin-binding region and they show defects in motor function. Therefore, the L1CD is not responsible for the major defects observed in L1(KO) mice, yet it is required for continued L1 protein expression and motor function in the adult.

A modifier locus on chromosome 5 contributes to L1 cell adhesion molecule X-linked hydrocephalus in mice.

Humans with L1 cell adhesion molecule (L1CAM) mutations exhibit X-linked hydrocephalus, as well as other severe neurological disorders. L1-6D mutant mice, which are homozygous for a deletion that removes the sixth immunoglobulin-like domain of L1cam, seldom display hydrocephalus on the 129/Sv background. However, the same L1-6D mutation produces severe hydrocephalus on the C57BL/6J background. To begin to understand how L1cam deficiencies result in hydrocephalus and to identify modifier loci that contribute to X-linked hydrocephalus by genetically interacting with L1cam, we conducted a genome-wide scan on F2 L1-6D mice, bred from L1-6D 129S2/SvPasCrlf and C57BL/6J mice. Linkage studies, utilizing chi-square tests and quantitative trait loci mapping techniques, were performed. Candidate modifier loci were further investigated in an extension study. Linkage was confirmed for a locus on chromosome 5, which we named L1cam hydrocephalus modifier 1 (L1hydro1), p = 4.04 X 10(-11).

FAK-MAPK-dependent adhesion disassembly downstream of L1 contributes to semaphorin3A-induced collapse.

Axonal receptors for class 3 semaphorins (Sema3s) are heterocomplexes of neuropilins (Nrps) and Plexin-As signalling coreceptors. In the developing cerebral cortex, the Ig superfamily cell adhesion molecule L1 associates with Nrp1. Intriguingly, the genetic removal of L1 blocks axon responses of cortical neurons to Sema3A in vitro despite the expression of Plexin-As in the cortex, suggesting either that L1 substitutes for Plexin-As or that L1 and Plexin-A are both required and mediate distinct roles. We report that association of Nrp1 with L1 but not Plexin-As mediates the recruitment and activation of a Sema3A-induced focal adhesion kinase-mitogen-activated protein kinase cascade. This signalling downstream of L1 is needed for the disassembly of adherent points formed in growth cones and subsequently their collapse response to Sema3A. Plexin-As and L1 are coexpressed and present in common complexes in cortical neurons and both dominant-negative forms of Plexin-A and L1 impair their response to Sema3A. Consistently, Nrp1-expressing cortical projections are defective in mice lacking Plexin-A3, Plexin-A4 or L1. This reveals that specific signalling activities downstream of L1 and Plexin-As cooperate for mediating the axon guidance effects of Sema3A.