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Oligodendrocyte contribution to RASopathy-associated neurological issues

   A common characteristic of RASopathies is the abnormal activation of the molecular pathway RAS/MAPK. Several reports, including my own, indicate that RAS-activating mutations in mouse oligodendrocytes (OLs) disrupt myelin structure in correlation with abnormal behavior. Increased activation of at least other two signal pathways - Nitric Oxide (NO) and Notch - participate in the mechanism downstream of RAS/MAPK activation. Additionally, RAS activation in OLs causes abnormalities in neighbor cells. 

  Interestingly, pharmacological control of RAS/MAPK, NO, and Notch pathways restores myelin structure and behavior. In order to better define the contribution of OLs to RASopathies, and to propose therapies for neurological issues, research goals of my lab include:

Signal Pathways Model.png

  1. Uncovering the molecular links between known and unknown pathways stimulated downstream of RAS activation in OLs.

  2. Defining the contribution of abnormal OL signal pathways in the context of germline RAS-activation; model mimicking human genetic diseases.

  3. Describing the impact of RASopathy mutations on motor skills and learning paradigms during the postnatal development and adulthood.

  4. Comparing the effects of specific mutations in modulators of the RAS/MAPK pathway, in the context of severity and progression of phenotypes.

  5. Identifying effective drugs targeting RAS/MAPK modulators to revert phenotypes in RASopathy models.    

Structural and functional cell-cell interactions in the White Matter

   Normal brain function relies on the establishment and maintenance of cell-cell communications. During development and after injury, newborn OLs form linear arrays in diverse WM tracts. Single astrocytes embedded within OL linear arrays have been described; however, the function of these heterocellular arrays remains largely unknown. My recent observations utilizing specific markers indicate that astrocytes embedded in OL linear arrays also contact blood vessels and axonal tracts through different processes. Interestingly, these Heterocellular Oligodendrocyte-associated Linear Arrays (HOLAs) are disrupted in RASopathy models, in which a RAS activating mutation was introduced to OLs. To define function and relevance of HOLAs in neurological diseases, further goals of my lab include:

Modified from Lopez-Juarez, et al., 2017

  1. To quantitively describe cell-cell interactions (glia-glia, glia-axon, and glia-vasculature) within HOLAs of adult WM tracts.

  2. To describe the integration of HOLAs during development of the corpus callosum and optic nerve.

  3. To analyze the impact of ablation of HOLA-associated astrocytes at the structural and functional level.

  4. To describe the mechanism for the disruption of HOLAs in mouse RASopathy models.

   To accomplish the above goals, my lab utilizes histological, biochemical, computational and behavioral analysis in wild type mice, as well as in models of Nf1, CS, and Nf1/CS. 

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