CELL ADHESION MOLECULE L1 AND MENTAL RETARDATION

Project: Research project

Description

Recent advances in the fields of neural cell adhesion molecules (CAMs) and human genetics have provided a unique opportunity to begin a careful cell biological study of the causes of two inherited X-linked diseases that produce mental retardation; X-linked hydrocephalus and MASA syndrome. It has been demonstrated that these syndromes are the result of mutations in the neural cell adhesion molecule L1. The possibility has also been raised that other X-linked forms of mental retardation, such as some cases of X-linked a specific mental retardation, are also due to mutations in L1. While the primary genetic defects in L1 are now known in several families, the reasons for the alterations in brain development are not clear. What is intriguing is that subtle differences in the form of L1 expressed appear to produce different phenotypes. L1 has been implicated in neuronal migration and in axon guidance. In most parts of the nervous system L1 is expressed on axons and growth cones and is believed to play an important role in providing a substrate for growth cone attachment as well as in mediating axon fasciculation. L1 is expressed by the vast majority of projection axons in the CNS and PNS and is also expressed by Schwann cells in the PNS. Due to its widespread expression in the developing nervous system it is likely to be an important player in the establishment of major fiber tracks and nerves. In vitro and in vivo experiments have shown that disruption of L1 function leads to significant alterations in the formation of both the CNS and PNS. Cell biological studies of L1 have revealed that this CAM has complex interactions with several intracellular and extracellular proteins. It has been reported that L1 binds extracellularly to L1, axonin-1, F3/F11, laminin and NCAM. Additionally, L1 is also capable of influencing intracellular second messenger systems. Crosslinking L1 with antibodies leads to change in intracellular pH, IP3 and CA++. L1 has at least two associated kinases that could be the initial players in initiating second messenger systems. The complex nature of L1, with its many functional domains, may explain the different phenotypes expressed by families with L1 defects. Therefore, we propose to examine in detail, using different cell biological assays, the functional capabilities of mutated L1 forms from human families and to correlate this with the human phenotypes. We will examine mutant L1-L1 binding and neurite outgrowth, mutant L1 interactions with their heterophilic binding partners and the ability of mutant L1 to mediate alterations in intracellular Ca++. This should provide a completely new level of understanding of these X-linked forms of mental retardation.
StatusFinished
Effective start/end date12/9/9411/30/98

Funding

  • National Institutes of Health
  • National Institutes of Health: $175,043.00
  • National Institutes of Health: $167,844.00

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Neural Cell Adhesion Molecule L1
Second Messenger Systems
X-Linked Mental Retardation
Intellectual Disability
Neural Cell Adhesion Molecules
Growth Cones
Phenotype
Nervous System
Contactin 2
Axons
Mutation
Schwann Cells
Medical Genetics
Cell Adhesion Molecules
Laminin
Nerve Fibers
Biological Assay
Phosphotransferases
Antibodies
Brain

ASJC

  • Medicine(all)
  • Neuroscience(all)