Counter-adhesion, mediated by the family of matricellular proteins, has been implicated in the transformation of cells into an intermediate state of adhesion that favors cellular functions related to locomotion. Despite a variety of locomotive events during myelin sheath formation by oligodendrocytes, the involvement of counter-adhesive mechanisms has not been characterized. We hypothesize, based on our preliminary data, that phosphodiesterase-1 alpha/autotaxin [PD-1 alpha/ATX (NPP-2)] is released by oligodendrocytes as a hitherto uncharacterized counter-adhesive component of the extracellular matrix (ECM) that is critically involved in regulating oligodendrocyte adhesion and myelin membrane formation.
In specific aim 1, we will investigate the role of metalloproteolytic activities in the generation of soluble oligodendrocyte-derived PD-1 alpha/ATX, since we have shown that the soluble form of this type II transmembrane protein functions as a counter-adhesive molecule and is present during the initial stages of CNS myelination.
In specific aim 2, we will determine the extent to which cytoskeleton-related mechanisms, similar to the ones observed for other matricellular proteins, contribute to PD-1 alpha/ATX's counter-adhesive effect toward oligodendrocytes. In these experiments, we will determine the involvement of integrins, the distribution of cytoskeletal proteins and the activation state of Rho-GTPases to PD-1 alpha/ATX-mediated counter-adhesion.
In specific aim 3, we will determine the extent to which proper myelin membrane formation is directly dependent on PD-1 alpha/ATX gene expression levels. In these studies we will analyze the effect of PD-1 alpha/ATX over and under expression on the ability of oligodendrocytes to generate myelin membranes in vitro and to myelinate axons in vivo in the brain of the dysmyelinating mouse mutant shiverer. In addition, we will generate and characterize transgenic mice, in which oligodendrocytes over express PD-1 alpha/ATX. Taken together, these studies will provide novel insight into the role of counter-adhesive molecules for oligodendrocyte function and likely provide novel targets for improving therapeutic strategies designed to stimulate remyelination under pathological conditions. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Utz, Ursula
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Virginia Commonwealth University
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Araújo, Sheila Espírito Santo; Mendonça, Henrique Rocha; Wheeler, Natalie A et al. (2017) Inflammatory demyelination alters subcortical visual circuits. J Neuroinflammation 14:162
Wheeler, Natalie A; Fuss, Babette; Knapp, Pamela E et al. (2016) HIV-1 Tat Inhibits Autotaxin Lysophospholipase D Activity and Modulates Oligodendrocyte Differentiation. ASN Neuro 8:
Wheeler, Natalie A; Fuss, Babette (2016) Extracellular cues influencing oligodendrocyte differentiation and (re)myelination. Exp Neurol 283:512-30
Wheeler, Natalie A; Lister, James A; Fuss, Babette (2015) The Autotaxin-Lysophosphatidic Acid Axis Modulates Histone Acetylation and Gene Expression during Oligodendrocyte Differentiation. J Neurosci 35:11399-414
Martinez-Lozada, Zila; Waggener, Christopher T; Kim, Karam et al. (2014) Activation of sodium-dependent glutamate transporters regulates the morphological aspects of oligodendrocyte maturation via signaling through calcium/calmodulin-dependent kinase II?'s actin-binding/-stabilizing domain. Glia 62:1543-1558
Waggener, Christopher T; Dupree, Jeffrey L; Elgersma, Ype et al. (2013) CaMKII? regulates oligodendrocyte maturation and CNS myelination. J Neurosci 33:10453-8
Yuelling, Larra W; Waggener, Christopher T; Afshari, Fatemah S et al. (2012) Autotaxin/ENPP2 regulates oligodendrocyte differentiation in vivo in the developing zebrafish hindbrain. Glia 60:1605-18
Dennis, Jameel; Morgan, Magdalena K; Graf, Martin R et al. (2012) P2Y12 receptor expression is a critical determinant of functional responsiveness to ATX's MORFO domain. Purinergic Signal 8:181-90
Lafrenaye, Audrey D; Fuss, Babette (2010) Focal adhesion kinase can play unique and opposing roles in regulating the morphology of differentiating oligodendrocytes. J Neurochem 115:269-82
Nogaroli, Luciana; Yuelling, Larra M; Dennis, Jameel et al. (2009) Lysophosphatidic acid can support the formation of membranous structures and an increase in MBP mRNA levels in differentiating oligodendrocytes. Neurochem Res 34:182-93

Showing the most recent 10 out of 14 publications