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Focal adhesion kinase can play unique and opposing roles in regulating the morphology of differentiating oligodendrocytes.

ABSTRACT: During development cells of the oligodendrocyte lineage undergo significant changes in morphology when they differentiate from migratory oligodendrocyte progenitors, which are mostly bipolar, into post-migratory pre-myelinating oligodendrocytes, which extend complex and expanded process networks, and then finally into mature oligodendrocytes, which generate myelin sheaths required for efficient signal propagation within the nervous system. This extensive morphological remodeling occurs in the context of a complex extracellular environment and requires significant rearrangement of the cell's cytoskeleton. The molecular mechanisms underlying this intricate integration of signals, however, remain poorly understood. A key regulator of extracellular matrix to cytoskeleton signaling is the non-receptor tyrosine kinase FAK (focal adhesion kinase). Here, we report that FAK can regulate the morphology of differentiating post-migratory pre-myelinating oligodendrocytes in a unique and opposing fashion that is dependent on the nature of the extracellular matrix and mediated largely by FAK's catalytic activity. More specifically, FAK was found to restrict process network expansion in the presence of fibronectin but to promote morphological maturation in the presence of laminin-2. In addition, FAK's restraining role predominated for postnatal day 3-derived cells, while its maturation promoting role prevailed for postnatal day 5-derived cells. Taken together, our findings reveal a complex role of FAK in regulating the morphology of post-migratory pre-myelinating oligodendrocytes.

SUBMITTER: Lafrenaye AD

PROVIDER: S-EPMC2939935 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Focal adhesion kinase can play unique and opposing roles in regulating the morphology of differentiating oligodendrocytes.

Lafrenaye Audrey D AD Fuss Babette B

Journal of neurochemistry 20100819 1

During development cells of the oligodendrocyte lineage undergo significant changes in morphology when they differentiate from migratory oligodendrocyte progenitors, which are mostly bipolar, into post-migratory pre-myelinating oligodendrocytes, which extend complex and expanded process networks, and then finally into mature oligodendrocytes, which generate myelin sheaths required for efficient signal propagation within the nervous system. This extensive morphological remodeling occurs in the co ...[more]

PMID: 20649846

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Project description:Chromatin modifications affect gene regulation in response to environmental stimuli in numerous biological processes. For example, N-acetyl-glucosamine and CO2 induce a morphogenetic conversion between white (W) and opaque (O) cells in MTL (mating-type locus) homozygous and heterozygous ( A: /α) strains of the human fungal pathogen Candida albicans Here, we identify 8 histone-modifying enzymes playing distinct roles in the regulation of W/O switching in MTL homozygous and heterozygous strains. Most strikingly, genetic removal of the paralogous genes RPD3 and RPD31, both of which encode almost identical orthologues of the yeast histone deacetylase (HDAC) Rpd3, reveals opposing roles in W/O switching of MTL A: /α strains. We show that Rpd3 and Rpd31 functions depend on MTL genotypes. Strikingly, we demonstrate that Rpd3 and Rpd31, which are almost identical except for a divergent C-terminal extension present in Rpd31, exert their functions in distinct regulatory complexes referred to as CaRpd3L and CaRpd31S complexes. Moreover, we identify the Candida orf19.7185 product Ume1, the orthologue of yeast Ume1, as a shared core subunit of CaRpd3L and CaRpd31S. Mechanistically, we show that the opposing roles of Rpd3 and Rpd31 require their deacetylase activities. Importantly, CaRpd3L interacts with the heterodimeric transcriptional repressor A: 1/α2, thus controlling expression of WOR1 encoding the master regulator of W/O switching. Thus, our work provides novel insight about regulation mechanisms of W/O switching in MTL A: /α strains. This is the first example of two highly conserved HDACs exerting opposing regulatory functions in the same process in a eukaryotic cell. RPD3-like histone deacetylases (also called class I HDACs) are conserved from unicellular eukaryotes to mammals. Specifically, the genome of the human fungal pathogen Candida albicans, the most frequent cause of invasive fungal infections of high morbidity and mortality, harbors two almost identical paralogous HDACs, Rpd3 and Rpd31. We show here for the first time that Rpd3 and Rpd31 acquired functional divergence related to a distinct C-terminal domain. Rpd3 and Rpd31 associate with different complexes in the control regions of the master regulator gene WOR1, which is required for white-opaque (W/O) morphogenesis, respectively. The ability to switch is important for fungal pathogenesis, since it enables distinct host niche colonization. This work is to the best of our knowledge the first description of two paralogous HDACs playing opposing functional roles in the same developmental process. Our work adds a new angle concerning the molecular understanding of HDACs in the regulation of cell fate decisions.

Dataset Information

Focal adhesion kinase can play unique and opposing roles in regulating the morphology of differentiating oligodendrocytes.

Publications

Focal adhesion kinase can play unique and opposing roles in regulating the morphology of differentiating oligodendrocytes.

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