CRASH Syndrome: Does It Teach Us about Neurotrophic Functions of Cell Adhesion Molecules?

Abstract

L1 cell adhesion molecule is a transmembrane glycoprotein of the immunoglobulin superfamily. L1 plays essential roles in normal development of the nervous system, and the mutations in the L1 gene are responsible for CRASH syndrome, a very rare inherited disorder characterized by corpus callosum hypoplasia, mental retardation, adducted thumbs, spastic paraplegia, and hydrocephalus. Here it is hypothesized that in the normal nervous system, the synthesis and neurotrophic function of L1 is controlled by a positive feedback loop, which consists of L1, L1 sheddases, γ-secretase, L1 extracellular domain (L1ED), L1 cytoplasmic domain (L1CD), and transcriptional factor Pax6. The mutations in L1ED or L1CD will disrupt this feedback loop and inhibit the synthesis and neurotrophic function of L1, therefore contributing to the severe phenotypes in CRASH syndrome. Supported by several lines of experimental evidence, this hypothesis has important implications for the therapy of CRASH syndrome by guiding the development of novel strategies to restore this positive feedback loop to recover the normal function of L1 in CRASH patients.

Keywords

L1 ectodomain shedding presenilin Pax6 neurotrophic transcription

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References

Cao X. , Südhof TC 2001. A transcriptionally active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293:115-20.

Fransen E. , Van Camp G. , Vits L. , Willems PJ 1997. L1-associated diseases: clinical geneticists divide, molecular geneticists unite. Hum Mol Genet 6:1625-32.

Gouveia RM , Morais VA , Peixoto C. , Sousa M. , Regalla M. , Alves PM, and others. 2007. Production and purification of functional truncated soluble forms of human recombinant L1 cell adhesion glycoprotein from Spodoptera frugiperda Sf9 cells. Protein Expr Purif 52:182-93.

Hambsch B. , Grinevich V. , Seeburg PH , Schwarz MK 2005. γ-Protocadherins, presenilin-mediated release of C-terminal fragment promotes locus expression. J Biol Chem 280: 15888-97.

Herron LR , Hill M. , Davey F. , Gunn-Moore FJ 2009. The intracellular interactions of the L1 family of cell adhesion molecules. Biochem J 419:519-31.

Maness PF , Schachner M. 2007. Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. Nat Neurosci 10:19-26.

Maretzky T. , Schulte M. , Ludwig A. , Rose-John S. , Blobel C. , Hartmann D., and others. 2005. L1 is sequentially processed by two differently activated metalloproteases and presenilin/ gamma-secretase and regulates neural cell adhesion, cell migration, and neurite outgrowth. Mol Cell Biol 25:9040-53.

Mechtersheimer S. , Gutwein P. , Agmon-Levin N. , Stoeck A. , Oleszweski M., and others. 2001. Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins. J Cell Biol 155:661-73.

Meech R. , Kallunki P. , Edelman GM , Jones FS 1999. A binding site for homeodomain and Pax proteins is necessary for L1 cell adhesion molecule gene expression by Pax-6 and bone morphogenetic proteins. PNAS 96:2420-5.

10.

Needham LK , Thelen K. , Maness PF 2001. Cytoplasmic domain mutations of the L1 cell adhesion molecule reduce L1-ankyrin interactions. J Neurosci 21:1490-500.

11.

Schmid RS , Maness PF 2008. L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth. Curr Opin Neurobiol 18:245-50.

12.

Xu Y. , Kim HS , Joo Y. , Choi Y. , Chang KA , Park CH, and others. 2007. Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3beta expression. Cell Death Differ 14:79-91.

13.

Zhang L. , Huang XH 2007. Screening and identification of interaction partner of cytoplasmic domain of L1. Prog Biochem Biophys 34:354-8.