Abnormalities in Neuronal Process Extension, Hippocampal Development, and the Ventricular System of L1 Knockout Mice

Abstract

In humans, mutations in the L1 cell adhesion molecule are associated with a neurological syndrome termed CRASH, which includes corpus callosum agenesis, mental retardation, adducted thumbs, spasticity, and hydrocephalus. A mouse model with a null mutation in the L1 gene (Cohen et al., 1997) was analyzed for brain abnormalities by Nissl and Golgi staining and immunocytochemistry. In the motor, somatosensory, and visual cortex, many pyramidal neurons in layer V exhibited undulating apical dendrites that did not reach layer I. The hippocampus of L1 mutant mice was smaller than normal, with fewer pyramidal and granule cells. The corpus callosum of L1-minus mice was reduced in size because of the failure of many callosal axons to cross the midline. Enlarged ventricles and septal abnormalities were also features of the mutant mouse brain. Immunoperoxidase staining showed that L1 was abundant in developing neurons at embryonic day 18 (E18) in wild-type cerebral cortex, hippocampus, and corpus callosum and then declined to low levels with maturation. In the E18 cortex, L1 colocalized with microtubule-associated protein 2, a marker of dendrites and somata. These new findings suggest new roles for L1 in the mechanism of cortical dendrite differentiation, as well as in guidance of callosal axons and regulation of hippocampal development. The phenotype of the L1 mutant mouse indicates that it is a potentially valuable model for the human CRASH syndrome.

Conditional deletion of L1CAM in human neurons impairs both axonal and dendritic arborization and action potential generation

“…Our results confirm a morphological phenotype previously observed in animal models (Dahme et al, 1997;Cohen et al, 1998;Demyanenko et al, 1999), but also presents an additional component in the human mutant neuron's reduced ability to generate APs.…”

β-Site Amyloid Precursor Protein (APP)-cleaving Enzyme 1 (BACE1)-deficient Mice Exhibit a Close Homolog of L1 (CHL1) Loss-of-function Phenotype Involving Axon Guidance Defects

“…Our examination of the published L1 Ϫ/Ϫ and CHL1 Ϫ/Ϫ phenotypes suggested that L1 Ϫ/Ϫ defects are much more severe than the mild axon guidance errors of the BACE1 null. L1 Ϫ/Ϫ mice exhibit severe brain deformities, including hypoplasia of the hippocampus, corticospinal tract, corpus callosum, cerebellar vermis, enlarged ventricles, and various behavioral abnormalities (47)(48)(49). However, CHL1 Ϫ/Ϫ and BACE1 Ϫ/Ϫ phenotypes appear nearly indistinguishable (31,32).…”

“…L1 Ϫ/Ϫ mice have hydrocephalus, enlarged ventricles, and severe hypoplasia of certain CNS structures (e.g. hippocampus, corpus callosum, corticospinal tract, and cerebellar vermis) (47)(48)(49), whereas CHL1 Ϫ/Ϫ mice exhibit relatively mild axon mis-targeting in the hippocampus and olfactory bulb (31,32). Because L1 Ϫ/Ϫ abnormalities are markedly more serious than those of BACE1 null, it appeared less likely that abrogation of BACE1 cleavage of L1 could be responsible for the axon guidance defects of the BACE1 Ϫ/Ϫ mice.…”

L1 cell adhesion molecule is not required for small-diameter primary afferent sprouting after deafferentation

“…Two different lines of mice lacking L1 have distinct developmental defects that display a reduced corticospinal tract and corpus callosum, exhibit less sensitivity to pain, enlarged ventricles, and errors in the topographical mapping of retinal axons in the superior colliculus (Cohen et al, 1997;Dahme et al, 1997;Demyanenko et al, 1999;Demyanenko and Maness et al, 2003).…”

“…Wild-type (L1+/+) and L1 mutant (Y/-; B6;129S7-L1cam tm1Sor ; Cohen et al, 1997) mice originally obtained from both Dr. Vance Lemmon (University of Miami, Miami, Florida) and Jackson Labs were maintained as a breeding colony at UCLA and genotyped as reported in Demyanenko et al (1999). Adult mice underwent unilateral, extradural dorsal rhizotomies as previously described in rats, although the deafferentation spanned from T10-L2 instead of the T12-L4 levels used previously (Runyan et al, 2005).…”