CRASH syndrome: does it teach us about neurotrophic functions of cell adhesion molecules?
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, gamma-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.
Zhang
Ling
L
Department of Neurology, Zhongda Hospital, Southeast University, Nanjing, China. zhangling9@hotmail.com
D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D040181:Genetic Diseases, X-Linked; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D053763:Presenilins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics / Q000378:metabolism
D005136:Eye Proteins; D018398:Homeodomain Proteins; D039842:Neural Cell Adhesion Molecule L1; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D053763:Presenilins; D012097:Repressor Proteins