Functional significance of L1 cell adhesion molecule in the brain development of L1-mutant mice

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In order to elucidate the pathogenetic mechanisms of hydrocephalus due to L1CAM gene mutations, we evaluated brain development spatiotemporally of both L1-null mutant mice and L1-6D mice devoid of 6th immunoglobulin domain of L1. Genetic background of them was C57BL/6. We performed morphological analyses of fetal brains from embryonic day (E) 12.5 to 16.5. Genetic typing was done using amniotic membranes by PCR method. Backcrossing the L1-6D mice onto the C57BL/6 strain (B6-L1-6D) produced embryonic lethality. The yield of B6-L1-6D male(-/Y) was 15% of the litter at E12.5 and 6% at birth, being higher than expected (25%). The yield of B6-L1KO was 13% at E12.5, 16% at E16.5 and 5% at birth, which suggested the factors leading to lethality might act at late embryonic phase. The brains of B6-L1-6D showed normal development, including retina, retinotectal tract, telencephalon, diencephalons, midbrain, brainstem, spinal cord and dorsal root ganglia at E12.5. The brains of B6-L1KO showed decreased number of TUJ1-immunoreactive ganglion cells of retina, poor growth of retinotectal tract and hypoplastic postoptic recess at E12.5, which was alleviated at E16.5. Further analyses using other methods such as in vivo electroporation with siRNA might be beneficial to understand functional significance of L1 during brain development.