The Hippo pathway member Nf2 is required for inner cell mass specification.

During mammalian development, the first two lineages to be specified are the trophectoderm (TE) and the inner cell mass (ICM). The Hippo pathway kinases Lats 1 and 2 (Lats1/2) and the transcriptional coactivator Yap play important roles in this specification process [1]. In outside cells of the embryo, Yap is nuclear localized and cooperates with Tead4 to induce the TE-specifying transcription factor Cdx2. In inside cells, Lats1/2 phosphorylate Yap and prevent its nuclear localization. The factors acting upstream of Lats1/2 and Yap in this context have not been identified. Here, we demonstrate that the upstream Hippo pathway member Nf2/Merlin is required for Lats1/2-dependent Yap phosphorylation in the preimplantation embryo. Injection of dominant-negative Nf2 mRNA causes Yap mislocalization and ectopic Cdx2 expression, effects that can be rescued by overexpression of Lats2 kinase. Zygotic Nf2 mutant blastocysts have mild defects in Yap localization and Cdx2 expression, but these become much more severe upon removal of both maternal and zygotic Nf2. The inside cells of maternal-zygotic mutants fail to establish a pluripotent ICM and form excess TE, resulting in peri-implantation lethality. Together, these data establish a clear role for Nf2 upstream of Yap in the preimplantation embryo and demonstrate that Hippo signaling is essential to segregate the ICM from the TE.

Cockburn K ，Biechele S ，Garner J ，Rossant J ... -  《-》

The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass.

Nishioka N ，Inoue K ，Adachi K ，Kiyonari H ，Ota M ，Ralston A ，Yabuta N ，Hirahara S ，Stephenson RO ，Ogonuki N ，Makita R ，Kurihara H ，Morin-Kensicki EM ，Nojima H ，Rossant J ，Nakao K ，Niwa H ，Sasaki H ... -  《-》

Inhibition of RHO-ROCK signaling enhances ICM and suppresses TE characteristics through activation of Hippo signaling in the mouse blastocyst.

Specification of the trophectoderm (TE) and inner cell mass (ICM) lineages in the mouse blastocyst correlates with cell position, as TE derives from outer cells whereas ICM from inner cells. Differences in position are reflected by cell polarization and Hippo signaling. Only in outer cells, the apical-basal cell polarity is established, and Hippo signaling is inhibited in such a manner that LATS1 and 2 (LATS1/2) kinases are prevented from phosphorylating YAP, a key transcriptional co-activator of the TE-specifying gene Cdx2. However, the molecular mechanisms that regulate these events are not fully understood. Here, we showed that inhibition of RHO-ROCK signaling enhances ICM and suppresses TE characteristics through activation of Hippo signaling and disruption of apical-basal polarity. Embryos treated with ROCK inhibitor Y-27632 exhibited elevated expression of ICM marker NANOG and reduced expression of CDX2 at the blastocyst stage. Y-27632-treated embryos failed to accumulate YAP in the nucleus, although it was rescued by concomitant inhibition of LATS1/2. Segregation between apical and basal polarity regulators, namely PARD6B, PRKCZ, SCRIB, and LLGL1, was dampened by Y-27632 treatment, whereas some of the polarization events at the late 8-cell stage such as compaction and apical localization of p-ERM and tyrosinated tubulin occurred normally. Similar abnormalities of Hippo signaling and apical-basal polarization were also observed in embryos that were treated with RHO GTPases inhibitor. These results suggest that RHO-ROCK signaling plays an essential role in regulating Hippo signaling and cell polarization to enable proper specification of the ICM and TE lineages.

Kono K ，Tamashiro DA ，Alarcon VB 《-》

WWC1 and NF2 Prevent the Development of Intrahepatic Cholangiocarcinoma by Regulating YAP/TAZ Activity through LATS in Mice.

Park J ，Kim JS ，Nahm JH ，Kim SK ，Lee DH ，Lim DS ... -  《-》

A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis.

YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are major downstream effectors of the Hippo pathway that influences tissue homeostasis, organ size, and cancer development. Aberrant hyperactivation of YAP/TAZ causes tissue overgrowth and tumorigenesis, whereas their inactivation impairs tissue development and regeneration. Dynamic and precise control of YAP/TAZ activity is thus important to ensure proper physiological regulation and homeostasis of the cells. Here, we show that YAP/TAZ activation results in activation of their negative regulators, LATS1/2 (large tumor suppressor 1/2) kinases, to constitute a negative feedback loop of the Hippo pathway in both cultured cells and mouse tissues. YAP/TAZ in complex with the transcription factor TEAD (TEA domain family member) directly induce LATS2 expression. Furthermore, YAP/TAZ also stimulate the kinase activity of LATS1/2 through inducing NF2 (neurofibromin 2). This feedback regulation is responsible for the transient activation of YAP upon lysophosphatidic acid (LPA) stimulation and the inhibition of YAP-induced cell migration. Thus, this LATS-mediated feedback loop provides an efficient mechanism to establish the robustness and homeostasis of YAP/TAZ regulation.

Moroishi T ，Park HW ，Qin B ，Chen Q ，Meng Z ，Plouffe SW ，Taniguchi K ，Yu FX ，Karin M ，Pan D ，Guan KL ... -  《-》