FatJ acts via the Hippo mediator Yap1 to restrict the size of neural progenitor cell pools

MRC Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, S10 2TN, UK.
Development (Impact Factor: 6.46). 05/2011; 138(10):1893-902. DOI: 10.1242/dev.064204
Source: PubMed


The size, composition and functioning of the spinal cord is likely to depend on appropriate numbers of progenitor and differentiated cells of a particular class, but little is known about how cell numbers are controlled in specific cell cohorts along the dorsoventral axis of the neural tube. Here, we show that FatJ cadherin, identified in a large-scale RNA interference (RNAi) screen of cadherin genes expressed in the neural tube, is localised to progenitors in intermediate regions of the neural tube. Loss of function of FatJ promotes an increase in dp4-vp1 progenitors and a concomitant increase in differentiated Lim1(+)/Lim2(+) neurons. Our studies reveal that FatJ mediates its action via the Hippo pathway mediator Yap1: loss of downstream Hippo components can rescue the defect caused by loss of FatJ. Together, our data demonstrate that RNAi screens are feasible in the chick embryonic neural tube, and show that FatJ acts through the Hippo pathway to regulate cell numbers in specific subsets of neural progenitor pools and their differentiated progeny.

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    • "In zebrafish, fat1 has been shown to bind scribble to influence Hippo signaling [25]. However, FAT4 is arguably the closest structural and functional mammalian ortholog of Drosophila Fat [24,26]. Nonetheless, recent findings have shown that a conditional knockout of FAT4 in mouse livers failed to result in liver overgrowth or tumorigenesis, obscuring the role of FAT4 in Hippo-mediated mammalian overgrowth [27]. "
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    ABSTRACT: Understanding the molecular nature of human cancer is essential to the development of effective and personalized therapies. Several different molecular signal transduction pathways drive tumorigenesis when deregulated and respond to different types of therapeutic interventions. The Hippo signaling pathway has been demonstrated to play a central role in the regulation of tissue and organ size during development. The deregulation of Hippo signaling leads to a concurrent combination of uncontrolled cellular proliferation and inhibition of apoptosis, two key hallmarks in cancer development. The molecular nature of this pathway was first uncovered in Drosophila melanogaster through genetic screens to identify regulators of cell growth and cell division. The pathway is strongly conserved in humans, rendering Drosophila a suitable and efficient model system to better understand the molecular nature of this pathway. In the present study, we review the current understanding of the molecular mechanism and clinical impact of the Hippo pathway. Current studies have demonstrated that a variety of deregulated molecules can alter Hippo signaling, leading to the constitutive activation of the transcriptional activator YAP or its paralog TAZ. Additionally, the Hippo pathway integrates inputs from a number of growth signaling pathways, positioning the Hippo pathway in a central role in the regulation of tissue size. Importantly, deregulated Hippo signaling is frequently observed in human cancers. YAP is commonly activated in a number of in vitro and in vivo models of tumorigenesis, as well as a number of human cancers. The common activation of YAP in many different tumor types provides an attractive target for potential therapeutic intervention.
    Clinical and Translational Medicine 07/2014; 3(1):25. DOI:10.1186/2001-1326-3-25
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    • "Opposing gradients of Dachsous and Fat contribute to the recognition of positional values and control organ size by regulating the Hippo signaling activity in leg development and regeneration (Bando et al., 2009). Although vertebrates have Dachsous and Fat homologs and some reports suggest that their signals are activated similarly (Skouloudaki et al., 2009; Van Hateren et al., 2011), how or whether Hippo is regulated by Dachsous/Fat signaling in vertebrates remains unclear (Halder and Johnson, 2011). In the mammalian epidermis, the cell density-dependent regulation of Yap1 is mediated by α-catenin (Schlegelmilch et al., 2011), suggesting that some other mechanism is responsible for transducing the Hippo pathway's function in position recognition. "
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    ABSTRACT: The Hippo signaling pathway is conserved from insects to mammals and is important for multiple processes, including cell proliferation, apoptosis and tissue homeostasis. Hippo signaling is also crucial for regeneration, including intercalary regeneration, of the whole body in the flatworm and of the leg in the cricket. However, its role in vertebrate epimorphic regeneration is unknown. Therefore, to identify principles of regeneration that are conserved among bilaterians, we investigated the role of Hippo signaling in the limb bud regeneration of an anuran amphibian, Xenopus laevis. We found that a transcription factor, Yap1, an important downstream effector of Hippo signaling, is upregulated in the regenerating limb bud. To evaluate Yap1’s function in limb bud regeneration, we made transgenic animals that expressed a dominant-negative form of Yap under a heat-shock promoter. Overexpression of a dominant-negative form of Yap in tadpoles reduced cell proliferation, induced ectopic apoptosis, perturbed the expression domains of limb-patterning genes including hoxa13, hoxa11, and shh in the regenerating limb bud. Transient expression of a dominant-negative Yap in transgenic tadpoles also caused limb bud regeneration defects, and reduced intercalary regeneration. These results indicate that Yap1 has a crucial role in controlling the limb regenerative capacity in Xenopus, and suggest that the involvement of Hippo signaling in regeneration is conserved between vertebrates and invertebrates. This finding provides molecular evidence that common principles underlie regeneration across phyla, and may contribute to the development of new therapies in regenerative medicine.
    Developmental Biology 04/2014; 388(1). DOI:10.1016/j.ydbio.2014.01.018 · 3.55 Impact Factor
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    • "Loop tail and neural tube abnormalities are also observed in Vangl2 mutant mice (43) and renal cystogenesis is synergistically enhanced in Fat4−/−Vangl2−/+ mice (42). Fat4 knockdown in neural tube results in an increase of a subset of neural progenitors and differentiated Lim1+/Lim2+ neurons via downregulation of Yap1 phosphorylation (44). FAT4 is involved in the maintenance of PCP as well as inhibition of YAP1-mediated cell proliferation (Fig. 3A). "
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    ABSTRACT: FAT1, FAT2, FAT3 and FAT4 are human homologs of Drosophila Fat, which is involved in tumor suppression and planar cell polarity (PCP). FAT1 and FAT4 undergo the first proteolytic cleavage by Furin and are predicted to undergo the second cleavage by γ‑secretase to release intracellular domain (ICD). Ena/VAPS‑binding to FAT1 induces actin polymerization at lamellipodia and filopodia to promote cell migration, while Scribble‑binding to FAT1 induces phosphorylation and functional inhibition of YAP1 to suppress cell growth. FAT1 is repressed in oral cancer owing to homozygous deletion or epigenetic silencing and is preferentially downregulated in invasive breast cancer. On the other hand, FAT1 is upregulated in leukemia and prognosis of preB‑ALL patients with FAT1 upregulation is poor. FAT4 directly interacts with MPDZ/MUPP1 to recruit membrane‑associated guanylate kinase MPP5/PALS1. FAT4 is involved in the maintenance of PCP and inhibition of cell proliferation. FAT4 mRNA is repressed in breast cancer and lung cancer due to promoter hypermethylation. FAT4 gene is recurrently mutated in several types of human cancers, such as melanoma, pancreatic cancer, gastric cancer and hepatocellular carcinoma. FAT1 and FAT4 suppress tumor growth via activation of Hippo signaling, whereas FAT1 promotes tumor migration via induction of actin polymerization. FAT1 is tumor suppressive or oncogenic in a context‑dependent manner, while FAT4 is tumor suppressive. Copy number aberration, translocation and point mutation of FAT1, FAT2, FAT3, FAT4, FRMD1, FRMD6, NF2, WWC1, WWC2, SAV1, STK3, STK4, MOB1A, MOB1B, LATS1, LATS2, YAP1 and WWTR1/TAZ genes should be comprehensively investigated in various types of human cancers to elucidate the mutation landscape of the FAT‑Hippo signaling cascades. Because YAP1 and WWTR1 are located at the crossroads of adhesion, GPCR, RTK and stem‑cell signaling network, cancer genomics of the FAT signaling cascades could be applied for diagnostics, prognostics and therapeutics in the era of personalized medicine.
    International Journal of Oncology 10/2012; 41(6). DOI:10.3892/ijo.2012.1669 · 3.03 Impact Factor
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