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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD039884-06
Application #
6861076
Study Section
Special Emphasis Panel (ZRG1-MDCN-7 (01))
Program Officer
Vitkovic, Ljubisa
Project Start
2001-04-02
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2007-03-31
Support Year
6
Fiscal Year
2005
Total Cost
$306,788
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
052780918
City
Miami
State
FL
Country
United States
Zip Code
33146
Kishimoto, Tomokazu; Itoh, Kyoko; Umekage, Masafumi et al. (2013) Downregulation of L1 perturbs neuronal migration and alters the expression of transcription factors in murine neocortex. J Neurosci Res 91:42-50
Dai, Jinxia; Dalal, Jasbir S; Thakar, Sonal et al. (2012) EphB regulates L1 phosphorylation during retinocollicular mapping. Mol Cell Neurosci 50:201-10
Gavert, Nancy; Ben-Shmuel, Amir; Lemmon, Vance et al. (2010) Nuclear factor-kappaB signaling and ezrin are essential for L1-mediated metastasis of colon cancer cells. J Cell Sci 123:2135-43
Tapanes-Castillo, Alexis; Weaver, Eli J; Smith, Robin P et al. (2010) A modifier locus on chromosome 5 contributes to L1 cell adhesion molecule X-linked hydrocephalus in mice. Neurogenetics 11:53-71
Nakamura, Yukiko; Lee, Suni; Haddox, Candace L et al. (2010) Role of the cytoplasmic domain of the L1 cell adhesion molecule in brain development. J Comp Neurol 518:1113-32
Yeaney, Natalie K; He, Min; Tang, Ningfeng et al. (2009) Ethanol inhibits L1 cell adhesion molecule tyrosine phosphorylation and dephosphorylation and activation of pp60(src). J Neurochem 110:779-90
Tyukhtenko, Sergiy; Deshmukh, Lalit; Kumar, Vineet et al. (2008) Characterization of the neuron-specific L1-CAM cytoplasmic tail: naturally disordered in solution it exercises different binding modes for different adaptor proteins. Biochemistry 47:4160-8
Bechara, Ahmad; Nawabi, Homaira; Moret, Frederic et al. (2008) FAK-MAPK-dependent adhesion disassembly downstream of L1 contributes to semaphorin3A-induced collapse. EMBO J 27:1549-62
Oliva Jr, Anthony A; Atkins, Coleen M; Copenagle, Lily et al. (2006) Activated c-Jun N-terminal kinase is required for axon formation. J Neurosci 26:9462-70
Tang, Ningfeng; He, Min; O'Riordan, Mary Ann et al. (2006) Ethanol inhibits L1 cell adhesion molecule activation of mitogen-activated protein kinases. J Neurochem 96:1480-90

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