Disruption of the mouse L1 gene leads to malformations of the nervous system

Abstract

The adhesion molecule L1 is a member of the immunoglobulin superfamily. L1 is involved in various recognition processes in the CNS and PNS, and binding to L1 can activate signal transduction pathways. Mutations in the human L1 gene are associated with a variable phenotype, including mental retardation and anomalous development of the nervous system, referred to as 'CRASH' (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus). We generated an animal model of these conditions by gene targetting. Mutant mice were smaller than wild-type and were less sensitive to touch and pain, and their hind-legs appeared weak and uncoordinated. The size of the corticospinal tract was reduced and, depending on genetic background, the lateral ventricles were often enlarged. Non-myelinating Schwann cells formed processes not associated with axons and showed reduced association with axons. In vitro, neurite outgrowth on an L1 substrate and fasciculation were impaired. The mutant mouse described here will help to elucidate the functions of L1 in the nervous system and how these depend on genetic influences.

Hereditary hydrocephalus internus in a laboratory strain of golden hamsters (Mesocricetus auratus)

“…A gene of the mutation ch was localized, which induces several skeletal developmental defects in addition to a lethal hydrocephalus (Hong et al, 1999). Mutant mice were generated by gene targeting to obtain an animal model of the human CRASH phenotype, which includes a hydrocephalus (Dahme et al 1997).…”

“…Not surprisingly therefore, it has been difficult to find single genes responsible for hydrocephalus in humans despite the evidence for genetic causes. The exception is one gene on the X-chromosome, L1-CAM, of which the associated protein and its function are known (Dahme et al, 1997;Forestier, 2003).…”

Cell biology of embryonic migration

“…(Carmeliet et al, 1999) L1-CAM Cell-cell adhesion Total Malformations of the nervous system, decreased nerve sensitivity, weak and uncoordinated hindlegs. (Dahme et al, 1997) Ate1 Arginyltransferase Total Embryonic lethality at E12-17 with defects in cardiovascular development and angiogenesis (Kwon et al, 2002) Calpain IV (Capn4) Protease Total Embryonic lethality at midgestation with defects in the cardiovascular system, (Arthur et al, 2000) Birth Defects Res C Embryo Today. Author manuscript; available in PMC 2009 June 1.…”

Disrupted Schwann cell–axon interactions in peripheral nerves of mice with altered L1-integrin interactions

“…Peripheral nerves in L1KO mice also show abnormalities with non-myelinating Schwann cells often failing to ensheath small caliber axons appropriately (Dahme et al, 1997;Haney et al, 1999), likely accounting for abnormal nociception in these mice (Thelin et al, 2003). In nerve transplant studies, loss of axonal-L1, but not Schwann cell-L1, reproduced the L1-deficient phenotype (Haney et al, 1999).…”

“…L1 knockout mice (L1KO mice) show hydrocephalus, reduced corticospinal tract, abnormal pyramidal decussation, ventricular dilatation, and hypoplasia of the cerebellar vermis (Dahme et al, 1997;Cohen et al, 1998;Fransen et al, 1998). Peripheral nerves in L1KO mice also show abnormalities with non-myelinating Schwann cells often failing to ensheath small caliber axons appropriately (Dahme et al, 1997;Haney et al, 1999), likely accounting for abnormal nociception in these mice (Thelin et al, 2003).…”