Ataxia and Abnormal Cerebellar Microorganization in Mice with Ablated Contactin Gene Expression

Abstract

Axon guidance and target recognition depend on neuronal cell surface receptors that recognize and elicit selective growth cone responses to guidance cues in the environment. Contactin, a cell adhesion/recognition molecule of the immunoglobulin gene superfamily, regulates axon growth and fasciculation in vitro, but its role in vivo is unknown. To assess its function in the developing nervous system, we have ablated contactin gene expression in mice. Contactin-/- mutants displayed a severe ataxic phenotype consistent with defects in the cerebellum and survived only until postnatal day 18. Analysis of the contactin-/- mutant cerebellum revealed defects in granule cell axon guidance and in dendritic projections from granule and Golgi cells. These results demonstrate that contactin controls axonal and dendritic interactions of cerebellar interneurons and contributes to cerebellar microorganization.

Disruption of axo–glial junctions causes cytoskeletal disorganization and degeneration of Purkinje neuron axons

“…CNTN mutants have striking defects in cerebellar development, including axonal swellings in Purkinje neurons. CNTN is expressed by several types of cerebellar neurons and has been proposed to play a role in mediating neurite outgrowth and neuronal interactions (37,38). However, CNTN mutant mice exhibit more widespread defects that seem specific to CNTN mutants because we did not observe any parallel fiber orientation defects in NCP1 and CGT mutants (38 and data not shown), suggesting that CNTN has additional functions which are independent of NCP1 and paranodal AGJs.…”

Contactin-1 regulates myelination and nodal/paranodal domain organization in the central nervous system

“…To assess the contribution of Contactin in central myelin formation, we analyzed Cntn1-KO mice between the onset of myelination at P10 up to P18, when the mutation is lethal (10). Absence of Contactin in Cntn1-KO mice was confirmed by immunostaining of optic nerve, cerebellum, and corpus callosum, and by Western blotting of whole-brain lysates ( Fig.…”

“…All experiments were approved by the Institutional Animal Care and Use Committee of Sanford-Burnham Medical Research Institute (La Jolla, CA). The derivation of mice homozygous for the mutant Contactin-1 (Cntn1) allele was described previously (10). Transgenic mice expressing GFP from the proteolipid promoter (PLP-GFP) were intercrossed with heterozygous Cntn1-KO mice to create homozygous Cntn1-KO and WT progeny expressing GFP in the oligodendrocyte lineage.…”

“…In this study, WT mice were analyzed at P10-30. Homozygous Cntn1-KO mice survive up to P18 (10) and were compared with WT littermates between P10 and P18.…”

“…Contactin is expressed by a diversity of neurons and contributes to the formation and function of neuronal connections (8)(9)(10). In myelinated peripheral nerves, Contactin is concentrated at axon membranes flanking the nodes of Ranvier, and serves an essential role in organizing the septate-like paranodal axoglial junctions (11,12).…”