The long-term goal of these studies is to gain insight into the role of counteradhesive molecules for oligodendrocyte function. Counteradhesion, mediated by the family of matricellular proteins, has been implicated in the transformation of cells into intermediate adhesive states that favor cellular functions related to locomotion. Despite of a variety of locomotive events during myelin sheath formation, the involvement of matricellular proteins has not been characterized. We hypothesize, based on our preliminary data, that phosphodiesterase-Ia/autotaxin [PD-Ia/ATX (NPP-2)] is released by oligodendrocytes as a hitherto uncharacterized matricellular component of the extracellular matrix that regulates the adhesive state of post-migratory oligodendrocytes and consequently determines their process remodeling capacity and thus the overall efficiency of myelin sheath formation. In, specific aim 1, we will investigate the role of metalloproteolytic activities in the generation of soluble, oligodendrocyte-derived PD-Ia/ATX, since it is the soluble form of this type II transmembrane protein that appears functionally active during myelination initiation.
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-Ia/ATX's counteradhesive effect toward oligodendrocytes. In these experiments, we will determine the involvement of functional active integrins, the redistribution of cytoskeletal proteins and the activation of Rho-GTPases for PD-Ia/ATX mediated counteradhesion. In the experiments to specific aim 3, we will determine the extent to which process outgrowth/remodeling and myelin membrane and sheath formation is directly dependent on PDIa/ATX expression levels. In these studies we will analyze PD-Ia/ATX over- and under-expressing oligodendrocytes for their capacity to generate complex process morphologies and myelin membrane structures in vitro and to myelinate axons in vivo in the brain of the dysmyelinating mouse mutant shiverer. In addition, we will characterize transgenic mice, in which oligodendrocytes over-express PD-la/ATX. These studies will provide novel insight into the molecular mechanisms that determine CNS myelination, and they may contribute to the development of novel therapeutic strategies designed to improve 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