CELL ADHESION MOLECULES IN NERVOUS SYSTEM DEVELOPMENT

Project: Research project

Project Details

Description

DESCRIPTION (From the Applicant's Abstract): The neural cell adhesion molecule
L1 is found on some classes of migrating neuronal precursors in the developing
nervous system and on almost all projection axons in both the central nervous
system and peripheral nervous system. Not surprisingly, it has been implicated
in the fasciculation of axon bundles and in migration of some neural precursors
in various in vitro systems. In the early 1990's it was shown that mutations in
the L1 gene in humans cause severe mental retardation (corpus callosum
hypoplasia, adducted thumbs, spastic paraplegia, and hydrocephalus). We have
analyzed individuals with different mutations in the L1 gene and discovered
that mutations that lead to a loss of L1 expression are much more severe than
mutations that only alter the cytoplasmic domain of L1. However, mutations of
the cytoplasmic domain are sufficient to cause axon guidance failures and
mental retardation. Recently, we and others have analyzed the L1 knock-out
mouse and discovered that it has a phenotype remarkably similar to humans with
X-linked hydrocephalus. This includes hydrocephalus, abnormal development of
the corticospinal tract, and hypoplasia of the cerebellar vermis and corpus
callosum. In this project we propose to test the hypothesis that L1 mediated
adhesion is essential for normal development of the cerebellar vermis and that
the function of the L1 cytoplasmic domain is essential for development of the
corticospinal tract. To do this we will generate new mouse lines with specific
alterations in the L1 cytoplasmic domain. We will also analyze mice in which
the 6th Ig domain of L1 has been removed, deleting the RGD sequence in L1,
allowing us to evaluate the difference between L1 homophilic binding and
L1-integrin interactions during brain development. Finally, we will undertake
the first careful analysis of cerebellar development in mice with altered or
absent L1.
StatusFinished
Effective start/end date4/2/013/31/07

Funding

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $306,788.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $259,301.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $306,788.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $47,956.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $309,825.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $309,825.00

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