The external cues that guide the migration of developing neurons and outgrowth of neurons upon differentiation have been intensely studied for decades. CXCR4, a chemokine receptor, has been implicated in the regulation of chemotaxis, neuronal migration, and axonal guidance. Neuroblastoma cells, which are of neural crest origin, are capable of differentiating into more mature sympathetic neurons in culture, and insulin-like growth factor I (IGF-1), has been shown to promote both migration and neurite outgrowth in these cells. In addition, neuroblastoma cells often express high levels of CXCR4, are responsive to CXCLI 2 and, depending upon the level of differentiation, are capable of producing fully extended axons. The mediator of the cytoskeletal changes seen in during process extension is actin polymerization. We have shown that in the neuroblastoma cell line, SHSY-5Y, both CXCR4 and IGF I receptors are involved in neuronal outgrowth, however, treatment with ligands for these receptors results in different cellular morphologies. CXCR4 stimulation stimulated the cells to take on a more differentiated neuronal form and directly involved actin, while IGF-IR stimulation resulted in a very immature neuronal morphology with shorter, broader processes. Based on these results, our overall hypothesis is that CXCR4 promotes neuronal migration and neurite extension through direct regulation of actin dynamics. Our preliminary data suggest that activation of CXCR4 by CXCL12 in cultured neuroblastoma cells promotes the elongation of neurites, and we have found CXCR4 along these projections. In this work we will be testing three specific hypotheses: 1) Cellular context, including the extracellular matrix present and the concentration of CXCL12 ligand to which the cells are exposed play a large role in determining the signaling pathways that are activated, and thereby the ability of the cells to migrate; 2) CXCR4 activation by CXCL12 promotes an increase in neurite length in neuroblastoma cells; 3) CXCR4 regulates elongation of neuronal processes through interaction with actin using the actinbinding protein Dbn; We will use immunocytochemistry/confocal microscopy, neurite analysis, and immunoprecipitation with cultured neuroblastoma and sympathetic neurons to test these hypotheses. Posttranslational modification of CXCR4 will be analyzed using Mass Spectroscopy.

Public Health Relevance

Neuronal migration during development is critical for the proper formation of nervous system structures and proper synaptic connections. Elucidating the mechanisms underlying CXCR4 mediated neuronal migration is mportant for both understanding normal development and determining strategies for correcting defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103653-03
Application #
8731950
Study Section
Special Emphasis Panel (ZRR1-RI-4)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
3
Fiscal Year
2014
Total Cost
$166,282
Indirect Cost
$50,000
Name
Delaware State University
Department
Type
DUNS #
114337629
City
Dover
State
DE
Country
United States
Zip Code
19901
Doherty, Tiffany S; Blaze, Jennifer; Keller, Samantha M et al. (2017) Phenotypic outcomes in adolescence and adulthood in the scarcity-adversity model of low nesting resources outside the home cage. Dev Psychobiol 59:703-714
Blaze, Jennifer; Asok, Arun; Borrelli, Kristyn et al. (2017) Intrauterine exposure to maternal stress alters Bdnf IV DNA methylation and telomere length in the brain of adult rat offspring. Int J Dev Neurosci 62:56-62
Shorey, Ryan C; Elmquist, Joanna; Gawrysiak, Michael J et al. (2017) A Randomized Controlled Trial of a Mindfulness and Acceptance Group Therapy for Residential Substance Use Patients. Subst Use Misuse 52:1400-1410
Medina, Alexandre E; Wozniak, Jeffrey R; Klintsova, Anna Y et al. (2017) Proceedings of the 2016 annual meeting of the Fetal Alcohol Spectrum Disorders Study Group. Alcohol 65:19-24
Blaze, Jennifer; Roth, Tania L (2017) Caregiver maltreatment causes altered neuronal DNA methylation in female rodents. Dev Psychopathol 29:477-489
Gawrysiak, Michael J; Jagannathan, Kanchana; Regier, Paul et al. (2017) Unseen scars: Cocaine patients with prior trauma evidence heightened resting state functional connectivity (RSFC) between the amygdala and limbic-striatal regions. Drug Alcohol Depend 180:363-370
Boppana, Sridhar; Lawal, Hakeem O (2017) Data on the specificity of an antibody to Drosophila vesicular acetylcholine transporter. Data Brief 15:257-261
Davis, Stephani A; Gan, Kok Ann; Dowell, James A et al. (2017) TDP-43 expression influences amyloid? plaque deposition and tau aggregation. Neurobiol Dis 103:154-162
Ruggiero, M J; Boschen, K E; Roth, T L et al. (2017) Sex Differences in Early Postnatal Microglial Colonization of the Developing Rat Hippocampus Following a Single-Day Alcohol Exposure. J Neuroimmune Pharmacol :
Boschen, K E; Klintsova, A Y (2017) Neurotrophins in the Brain: Interaction With Alcohol Exposure During Development. Vitam Horm 104:197-242

Showing the most recent 10 out of 86 publications