Background:The neural cell adhesion molecule L1 is important in the developing and adult nervous system. Results: L1 stimulation leads to sumoylation and proteolytic processing of L1 and translocation of a sumoylated transmembrane fragment to the nucleus. Conclusion: Sumoylation and nuclear localization of the L1 fragment are required for L1-dependent functions. Significance: Unraveling the molecular mechanisms underlying L1-activated cellular responses helps understanding L1-linked disorders.

Several L1-related adhesion molecules, expressed in a well-coordinated temporospatial pattern during development, are important for fine tuning of specific cerebellar circuitries. We tested the hypothesis that CHL1, the close homologue of L1, abundantly expressed in the developing and adult cerebellum, is also required for normal cerebellar histogenesis. We found that constitutive ablation of CHL1 in mice caused significant loss (20-23%) of Purkinje and granule cells in the mature 2-month-old cerebellum. The ratio of stellate/basket interneurons to Purkinje cells was abnormally high (+38%) in CHL1-deficient (CHL1-/-) mice compared with wild-type (CHL1+/+) littermates, but the gamma-aminobutyric acid (GABA)ergic synaptic inputs to Purkinje cell bodies and dendrites were normal, as were numbers of Golgi interneurons, microglia, astrocytes, and Bergmann glia. Purkinje cell loss occurred before the first postnatal week and was associated with enhanced apoptosis, presumably as a consequence of CHL1 deficiency in afferent axons. In contrast, generation of granule cells, as indicated by in vivo analyses of cell proliferation and death, was unaffected in 1-week-old CHL1-/- mice, but numbers of migrating granule cells in the molecular layer were increased. This increase was likely related to retarded cell migration because CHL1-/- granule cells migrated more slowly than CHL1+/+ cells in vitro, and Bergmann glial processes guiding migration in vivo expressed CHL1 in wild-type mice. Granule cell deficiency in adult CHL1-/- mice appeared to result from decreased precursor cell proliferation after the first postnatal week. Our results indicate that CHL1 promotes Purkinje and granule cell survival and granule cell migration during cerebellar development.

Failure of the mammalian central nervous system (CNS) to regenerate effectively after injury leads to mostly irreversible functional impairment. Gold nanoparticles (AuNPs) are promising candidates for drug delivery in combination with tissue-compatible reagents, such as polyethylene glycol (PEG). PEG administration in CNS injury models has received interest for potential therapy, but toxicity and low bioavailability prevents clinical application. Here we show that intraspinal delivery of PEG-functionalized 40-nm-AuNPs at early stages after mouse spinal cord injury is beneficial for recovery. Positive outcome of hind limb motor function was accompanied by attenuated inflammatory response, enhanced motor neuron survival, and increased myelination of spared or regrown/sprouted axons. No adverse effects, such as body weight loss, ill health, or increased mortality were observed. We propose that PEG-AuNPs represent a favorable drug-delivery platform with therapeutic potential that could be further enhanced if PEG-AuNPs are used as carriers of regeneration-promoting molecules.