Severe hydrocephalus in L1-deficient mice

The neural adhesion molecule L1, a member of the immunoglobulin superfamily of cell recognition molecules, performs important functions in the developing and adult nervous system. This view is confirmed by the fact that mutations in the human L1 gene cause a severe neurological disease, termed CRASH (acronym for: corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus). X-linked hydrocephalus is certainly the most prominent Symptom of CRASH syndrome. Mouse mutants deficient in L1 also develop enlarged ventricles. Here, we report that ventricular dilation in L1-deficient mice is not correlated with stenosis of the aqueduct of Sylvius nor with ultrastructural abnormalities of ependymal cells lining the lateral ventricles or the aqueduct. However, a few L1 mutant mice displayed severe hydrocephalus, characterized by a significant enlargement of the skull and an almost complete atrophy of the cerebral cortex. The aqueduct of these severely affected animals was completely closed. Since mutant animals from two independently generated L1-deficient mouse lines displayed a similar phenotype, we consider severe hydrocephalus as a specific consequence of L1-deficiency. However, results of the present study also indicate that severe hydrocephalus represents a secondary rather than a primary defect of the L1 mutation; our combined data suggest that deformations of the brain as a result of massively enlarged ventricles secondarily cause stenosis of the aqueduct and subsequently high pressure hydrocephalus. (C) 2001 Elsevier Science B.V. All rights reserved.