Project: Research project

Project Details


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.
Effective start/end date12/9/9411/30/98


  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke


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