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YAP/TAZ control peripheral myelination by regulating Schwann cell proliferation and the expression of laminin receptors

ABSTRACT: Myelination is essential for nervous system function. Schwann cells interact with neurons and with the basal lamina to sort and myelinate axons, using known receptors and signaling pathways. In contrast, the transcriptional control of axonal sorting and the role of mechano-transduction in myelination are largely unknown. Yap and Taz are effectors of the Hippo pathway that integrate chemical and mechanical signals in cells. Here, we describe a previously unknown role for the Hippo pathway in myelination. Using conditional mutagenesis in mice we show that Taz is required in Schwann cells for radial sorting and myelination. Yap is redundant with Taz as ablation of both Yap and Taz abolishes radial sorting. Yap/Taz regulate Schwann cell proliferation and transcription of basal lamina receptors, both necessary for proper radial sorting of axons, and subsequent myelination. These data link transcriptional effectors of the Hippo pathway and of mechanotransduction to myelin formation in Schwann cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE79115 | GEO | 2016/06/06

SECONDARY ACCESSION(S): PRJNA314975

REPOSITORIES: GEO

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A Reciprocal Regulatory Loop Between TAZ/YAP and G protein Gαs Regulates Schwann Cell Proliferation and Differentiation

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2017-04-26 | GSE94990 | GEO

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Project description:Hippo effectors Yap and Taz, Vgll1-4 and Tead 1-4 transcription factors have been linked to satellite cell/ myoblast proliferation and differentiation, muscle function and disease. The molecular function of Vgll3 in skeletal muscle stem cells was investigated using analysis of gene expression by microarrays to determine Vgll3 mediated gene expression changes and compare those to previously determined Taz and Yap mediated changes. Satellite cell-derived myoblasts were transduced with Vgll3 retrovirus for 24h or 48h, with empty retrovirus vector as control. Triplicate microarray analysis of empty vector controls and Vgll3 transgenic primary myoblasts were conducted.

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2017-05-17 | E-MTAB-5217 | biostudies-arrayexpress

Ablation of Dicer from murine Schwann cells increases their proliferation while blocking myelination

Project description:The myelin sheaths that surround the thick axons of the peripheral nervous system are produced by the highly specialized Schwann cells. Differentiation of Schwann cells and myelination occur in discrete steps. Each of these requires coordinated expression of specific proteins in a precise sequence, yet the regulatory mechanisms controlling protein expression during these events are incompletely understood. Here we report that Schwann cell-specific ablation of the enzyme Dicer1, which is required for the production of small non-coding regulatory microRNAs, fully arrests Schwann cell differentiation, resulting in early postnatal lethality. Dicer-/- Schwann cells had lost their ability to myelinate, yet were still capable of sorting axons. Both cell death and, paradoxically, proliferation of immature Schwann cells was vastly enhanced, suggesting that their terminal differentiation is triggered by growth-arresting regulatory microRNAs. Using microRNA microarrays, we identified 16 miRNAs that are upregulated upon myelination and whose expression is controlled by Dicer in Schwann cells. This set of microRNAs appears to drive Schwann cell differentiation and myelination of peripheral nerves, thereby fulfilling a crucial function for survival of the organism. Samples representing Schwann cell-specific ablation of the enzyme Dicer1 and wild type controls at developmental stages E17 and P4. Geometric mean-averaged data linked below as supplementary file.

2010-12-01 | E-GEOD-22023 | biostudies-arrayexpress

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Project description:The Hippo pathway plays an important role in regulating tissue homeostasis, and its effectors YAP and TAZ are responsible for mediating the vast majority of its physiological functions. Although YAP and TAZ are thought to be largely redundant and similarly regulated by Hippo signaling, they have developmental, structural, and physiological differences which suggest there may be differences in their regulation and downstream functions. To better understand the functions of YAP and TAZ in the Hippo pathway, we generated knockout cells and evaluated them in response to many conditions and stimuli. Here, we used RNA-seq to identify and compare differences in the transcriptional profiles between the YAP and TAZ.

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Muscle stems cell LC-MS - Common and Distinctive Functions of the Hippo Effectors Taz and Yap in Skeletal Muscle Stem Cell Function

Project description:Abstract Hippo pathway downstream effectors Yap and Taz play key roles in cell proliferation and regeneration, regulating gene expression especially via interaction with Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analysed Taz in vivo and ex vivo in comparison to Yap. Taz was expressed in activated satellite cells. siRNA knockdown or constitutive expression of wildtype or constitutively active TAZ mutants showed that TAZ promoted proliferation, a function that was shared with YAP. However, at later stages of myogenesis, TAZ also enhanced myogenic differentiation of myoblasts, whereas YAP inhibits such differentiation. Functionally, while muscle growth was mildly affected in Taz (gene symbol Wwtr1-/-) knockout mice, there were no overt effect on regeneration. However, conditional knockout of Yap in satellite cells of Pax7Cre-ERT2/+ : Yapflox/flox : Rosa26Lacz mice produced a marked regeneration deficit. To identify potential mechanisms, microarray analysis showed many common Taz/Yap targets, but Taz also regulates some genes independently of Yap, including myogenic genes such as Pax7, Myf5 and Myod1. Proteomic analysis of Yap/Taz revealed many common binding partners, but Taz also interacts with proteins distinct from Yap, that are mainly involved in myogenesis and aspects of cytoskeleton organization. Neither TAZ nor YAP bind members of the Wnt destruction complex but both extensively changed expression of Wnt and Wnt-cross talking genes with known roles in myogenesis. Finally, TAZ operates through Tead4 to enhance myogenic differentiation. In summary, Taz and Yap have overlapping functions in promoting myoblast proliferation but Taz then switches to promote myogenic differentiation.

2017-06-13 | PXD005751 | Pride

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