CHL1 (Close Homolog of L1) is an integrin-interacting cell recognition molecule related to the L1 cell adhesion molecule with a potential role in area-specific development of the neocortex. Mutation of the CHL1 gene (CALL) in humans is associated with the 3p-syndrome of mental retardation. CHL1 is expressed in a high caudal to low rostral gradient in cortical precursors during radial migration and in differentiating pyramidal neurons. Preliminary results show CHL1 knockout mice exhibit area- and lamina-specific abnormalities in radial migration and apical dendrite projection of pyramidal cells, and topographic mapping errors of thalamocortical axons. The hypothesis to be tested is that CHL1 modulates radial migration of cortical neurons in the mouse neocortex with consequences on dendrite projection and thalamocortical mapping.
Aims are: (1) To define the area- and lamina-specific distribution of cortical neurons and their dendritic development in homozygous and heterozygous CHL1 knockout mice and to assess the interaction of CHL1 with L1 in double mutant mice. A role for CHL1 in Semaphorin 3A-induced dendritic projection and branching of pyramidal neurons will be studied in cortical slices. (2) To determine the cellular mechanism of CHL1 in radial migration of cortical neurons in the posterior neocortex by BrdU labeling in vivo and in brain slice assays by time lapse videomicroscopy. (3) To investigate the molecular mechanism of CHL1 in intracellular signaling through intermediates (Src, Rac, Pak, ERK1,2) important for adhesion dynamics. (4) To identify topographic mapping defects in the thalamocortical projection of CHL1-/- mice by axon tracing in vivo and to analyze CHL1 function in thalamic axon guidance by axon tracing in embryos and a novel telencephalic whole mount assay. This investigation can reveal new molecular determinants and novel mechanisms governing cortical area development and provide insight into the pathology associated with mental retardation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049109-02
Application #
7014058
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Riddle, Robert D
Project Start
2005-04-01
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$263,753
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Biochemistry
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Demyanenko, Galina P; Siesser, Priscila F; Wright, Amanda G et al. (2011) L1 and CHL1 Cooperate in Thalamocortical Axon Targeting. Cereb Cortex 21:401-12
Demyanenko, Galina P; Riday, Thorfinn T; Tran, Tracy S et al. (2011) NrCAM deletion causes topographic mistargeting of thalamocortical axons to the visual cortex and disrupts visual acuity. J Neurosci 31:1545-58
Demyanenko, G P; Halberstadt, A I; Rao, R S et al. (2010) CHL1 cooperates with PAK1-3 to regulate morphological differentiation of embryonic cortical neurons. Neuroscience 165:107-15
Schmid, Ralf S; Maness, Patricia F (2008) L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth. Curr Opin Neurobiol 18:245-50
Schlatter, Monika C; Buhusi, Mona; Wright, Amanda G et al. (2008) CHL1 promotes Sema3A-induced growth cone collapse and neurite elaboration through a motif required for recruitment of ERM proteins to the plasma membrane. J Neurochem 104:731-44
Wright, Amanda G; Demyanenko, Galina P; Powell, Ashton et al. (2007) Close homolog of L1 and neuropilin 1 mediate guidance of thalamocortical axons at the ventral telencephalon. J Neurosci 27:13667-79
Maness, Patricia F; Schachner, Melitta (2007) Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. Nat Neurosci 10:19-26
Panicker, Anitha K; Buhusi, Mona; Erickson, Ann et al. (2006) Endocytosis of beta1 integrins is an early event in migration promoted by the cell adhesion molecule L1. Exp Cell Res 312:299-307
Demyanenko, Galina P; Halberstadt, Ari I; Pryzwansky, Katherine B et al. (2005) Abnormal neocortical development in mice lacking cGMP-dependent protein kinase I. Brain Res Dev Brain Res 160:1-8