YAP regulates neuronal differentiation through Sonic hedgehog signaling pathway

Lin, Yi Ting; Ding, Jing-Ya; Li, Ming Yang; Yeh, Tien Shun; Wang, Tsu Wei; Yu, Jenn Yah

doi:10.1016/j.yexcr.2012.05.005

Cited by 61 publications

(98 citation statements)

References 71 publications

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“…While oncogenic signals arising from YAP promote excessive proliferation (22,23,26), YAP can also promote cell death via a p73-dependent pathway (27)(28)(29)(30). YAP also has been shown to play a role in myoblast (31) and neuronal stem cell (32,33) differentiation. Additionally, recent evidence suggests that YAP is involved in cell survival in Wnt-and ␤-catenin-dependent colorectal cancers (34).…”

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confidence: 99%

Polyomavirus Small t Antigen Interacts with Yes-Associated Protein To Regulate Cell Survival and Differentiation

Hwang

Fernando

Faure

et al. 2014

J Virol

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Murine polyomavirus small t antigen (PyST) regulates cell cycle, cell survival, apoptosis, and differentiation and cooperates with middle T antigen (MT) to transform primary cells in vitro and in vivo. Like all polyomavirus T antigens, PyST functions largely via its interactions with host cell proteins. Here, we show that PyST binds both Yes-associated protein 1 (YAP1) and YAP2, integral parts of the Hippo signaling pathway, which is a subject of increasing interest in human cancer. The transcription factor TEAD, which is a known target of YAP, is also found in PyST complexes. PyST enhanced YAP association with protein phosphatase 2A (PP2A), leading to decreased YAP phosphorylation. PyST increased YAP levels by decreasing its degradation. This effect was mediated by a reduction in YAP association with ␤-transducin repeat protein (␤TRCP), which is known to regulate YAP turnover in a phosphorylation-dependent manner. Genetic analysis has identified PyST mutants defective in YAP binding. These mutants demonstrated that YAP binding is important for PyST to block myoblast differentiation and to synergize with the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) to promote cell death in 3T3-L1 preadipocytes placed under differentiation conditions. In addition to YAP binding, both of these phenotypes require PyST binding to PP2A. IMPORTANCEThe Hippo/YAP pathway is a highly conserved cascade important for tissue development and homeostasis. Defects in this pathway are increasingly being associated with cancer. Polyomavirus small t antigen is a viral oncogene that cooperates with middle T antigen in transformation. On its own, small t antigen controls cell survival and differentiation. By binding YAP, small t antigen brings it together with protein phosphatase 2A. This work shows how this association of small t antigen with YAP is important for its effects on cell phenotype. It also suggests that PyST can be used to characterize cellular processes that are regulated by YAP.

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mentioning

confidence: 99%

Polyomavirus Small t Antigen Interacts with Yes-Associated Protein To Regulate Cell Survival and Differentiation

Hwang

Fernando

Faure

et al. 2014

J Virol

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“…6). YAP activity is decreased during mammalian neurogenesis (19,36,37) in conjunction with Sonic Hedgehog (36,37) and Smad (38) signaling pathways, which are ubiquitous targets of soluble factors used to promote neuronal differentiation of hES cells (39)(40)(41)(42)(43)(44)(45)(46).…”

Section: Resultsmentioning

confidence: 99%

Substratum-induced differentiation of human pluripotent stem cells reveals the coactivator YAP is a potent regulator of neuronal specification

Musah¹,

Wrighton

Zaltsman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

159

174

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Physical stimuli can act in either a synergistic or antagonistic manner to regulate cell fate decisions, but it is less clear whether insoluble signals alone can direct human pluripotent stem (hPS) cell differentiation into specialized cell types. We previously reported that stiff materials promote nuclear localization of the Yes-associated protein (YAP) transcriptional coactivator and support long-term self-renewal of hPS cells. Here, we show that even in the presence of soluble pluripotency factors, compliant substrata inhibit the nuclear localization of YAP and promote highly efficient differentiation of hPS cells into postmitotic neurons. In the absence of neurogenic factors, the effective substrata produce neurons rapidly (2 wk) and more efficiently (>75%) than conventional differentiation methods. The neurons derived from substrate induction express mature markers and possess action potentials. The hPS differentiation observed on compliant surfaces could be recapitulated on stiff surfaces by adding small-molecule inhibitors of F-actin polymerization or by depleting YAP. These studies reveal that the matrix alone can mediate differentiation of hPS cells into a mature cell type, independent of soluble inductive factors. That mechanical cues can override soluble signals suggests that their contributions to early tissue development and lineage commitment are profound.H uman pluripotent stem (hPS) cells, which include human embryonic (hES) and human induced pluripotent stem cells, possess the remarkable capacity to self-renew indefinitely and differentiate into almost any specialized cell type (1, 2). They represent a potentially unlimited supply of cells for regenerative medicine, drug screening, and studies of human development. These applications require efficient and reproducible conditions to direct hPS cell differentiation into specialized cell types, including neuronal cells. To date, the focus has been on identifying soluble factors, such as growth factors and small molecules, that can influence hPS cell differentiation. The ability of insoluble signals to promote hPS cell-lineage specification remains less clear.Studies in murine ES cells (3, 4) and tissue-specific stem cells (5-10) indicate that the adhesive and mechanical properties of the substratum used can influence cell fate decisions (11). For example, human mesenchymal stem (hMS) cells are sensitive to changes in substrate elasticity and respond by differentiating toward distinct cell lineages depending on the stiffness of the matrix (5). These hMS cells, however, tend to exist in heterogeneous cell populations and lack a specific and unique cell characterization marker (12). Their differentiation capacity is restricted to a few tissues that arise from the mesoderm lineage, such as bone, fat, and cartilage. Indeed, there are questions about whether these cells undergo transdifferentiation to cell types, such as neurons (12)(13)(14). With the unique ability to differentiate into almost any cell type, hPS cells serve as an excellent model for und...

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“…The multiple roles for Smed-yki may be attributed to its ability to bind to various transcription factors and cooperate with many key developmental signaling cascades, such as TGFβ, Hedgehog, WNT/β-catenin, and EGFR signaling (Hong and Guan, 2012;Lin et al, 2012;Reddy and Irvine, 2013;Varelas et al, 2010;Varelas and Wrana, 2012;Zhang et al, 2009). Whether these interactions and downstream targets are also conserved in planarians or work in tissue-specific contexts remains to be elucidated, and planarians are a powerful model system to dissect the multi-faceted roles of YKI signaling.…”

Section: An Evolutionary Conserved Role For Yki In Excretory Systemsmentioning

confidence: 99%

Planarian yorkie/YAP functions to integrate adult stem cell proliferation, organ homeostasis and maintenance of axial patterning

Lin

Pearson

2014

Development

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During adult homeostasis and regeneration, the freshwater planarian must accomplish a constant balance between cell proliferation and cell death, while also maintaining proper tissue and organ size and patterning. How these ordered processes are precisely modulated remains relatively unknown. Here we show that planarians use the downstream effector of the Hippo signaling cascade, yorkie (yki; YAP in vertebrates) to control a diverse set of pleiotropic processes in organ homeostasis, stem cell regulation, regeneration and axial patterning. We show that yki functions to maintain the homeostasis of the planarian excretory (protonephridial) system and to limit stem cell proliferation, but does not affect the differentiation process or cell death. Finally, we show that Yki acts synergistically with WNT/β-catenin signaling to repress head determination by limiting the expression domains of posterior WNT genes and that of the WNTinhibitor notum. Together, our data show that yki is a key gene in planarians that integrates stem cell proliferation control, organ homeostasis, and the spatial patterning of tissues.

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YAP regulates neuronal differentiation through Sonic hedgehog signaling pathway

Cited by 61 publications

References 71 publications

Polyomavirus Small t Antigen Interacts with Yes-Associated Protein To Regulate Cell Survival and Differentiation

Polyomavirus Small t Antigen Interacts with Yes-Associated Protein To Regulate Cell Survival and Differentiation

Substratum-induced differentiation of human pluripotent stem cells reveals the coactivator YAP is a potent regulator of neuronal specification

Planarian yorkie/YAP functions to integrate adult stem cell proliferation, organ homeostasis and maintenance of axial patterning

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