Mutant FGFR3 restricts bone yet expands brain via ERK-mediated self-repression
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE316124 | GEO | 2026/01/16
REPOSITORIES: GEO
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Project description:The signaling pathways governing cortical neurogenesis and gliogenesis in mice are well-defined, yet how they integrate to control the lineage progression of cortical radial glia (RGs) remains incompletely understood. Here, using mouse genetic models, it is demonstrated that ERK and PKA signaling cooperate to preserve the neurogenic capacity of cortical RGs by suppressing the gliogenic pathways YAP/TAZ and SHH. Specifically, YAP/TAZ signaling drives cortical RGs toward an ependymal fate, while SHH signaling promotes the generation of tripotential intermediate progenitor cells that produce cortical astrocytes and oligodendrocytes, and olfactory bulb interneurons. Reanalysis of published human cortical scRNA-seq data further revealed that the functional roles of these signaling pathways are conserved between mouse and human cortical RGs. Furthermore, human cortical outer RGs acquire dominant ERK/PKA signaling through a self-reinforcing loop that suppresses both YAP and SHH signaling, markedly enhancing self-renewal and extending neurogenesis. Thus, a tripartite network of ERK/PKA, YAP/TAZ, and SHH whose cross-repressive logic coordinates neurogenesis with gliogenesis and may underlie evolutionary expansion, providing a framework for understanding cortical development and evolution, is identified.
2025-07-01 | GSE293205 | GEO
Project description:Human exceptional cognition stems from evolutionarily derived cortical adaptations that drive expansive neurogenesis. Deciphering these mechanisms is crucial for understanding mammalian cortical evolution. In this study, we employ the ferret model to comprehensively map molecular profiles and lineage dynamics of cortical radial glia (RGs). By applying scRNA-Seq to ferret and human cortices, we identify conserved regulatory programs underlying cortical neurogenesis and gliogenesis in mammals. Through integrated scRNA-Seq, BrdU pulse-chase labeling, and immunohistochemical approaches, we demonstrate that, similar to their human counterparts, ferret cortical outer radial glia (oRGs), exhibit enhanced ERK and PKA signaling. ERK and PKA act in a mutually reinforcing manner to boost oRG self-renewal and neurogenesis, while inhibiting gliogenesis and prolonging the neurogenic period. Furthermore, we identify regional specialization within cortical gliogenic RGs: YAP/TAZ activation drives ventricular zone truncated radial glia (tRGs) toward ependymal fate in medial cortex, whereas SHH signaling instructs lateral cortical tRGs to generate tripotential intermediate progenitor cells, which serve as a shared source of astrocytes, oligodendrocytes, and olfactory bulb interneurons. Our data support a model in which mammalian cortical neurogenesis, gliogenesis, and evolutionary expansion are co-regulated through an integrated signaling network involving ERK, PKA, YAP/TAZ, and SHH. These findings provide key insights into the molecular and cellular mechanisms driving cortical development and evolution.
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Project description:The NF2 gene, which encodes the Merlin protein, is a bona fide tumor suppressor whose mutations underlie inherited tumor syndrome Neurofibromatosis Type 2 (NF2). Recent large-scale genome sequencing studies have also identified NF2 as one of the most frequently mutated genes in VHL-wild-type kidney cancers. Even though a wide array of downstream signaling pathways has been described for Merlin/NF2, the molecular mechanisms underpinning the growth and survival of NF2 mutant tumors remain poorly understood. Using an inducible orthotopic kidney tumor model, we demonstrate for the first time that silencing of YAP/TAZ is sufficient to induce regression of pre-established NF2 deficient kidney tumors. Mechanistically, we show that YAP/TAZ ablation severely diminishes glycolysis by downregulating the transcription of several glycolytic enzymes and growth factors and RTK-PI3K-AKT signaling, resulting in growth arrest. On the other hand, YAP/TAZ depletion significantly increases mitochondrial respiration and overproduction of mitochondrial ROS, resulting in redox imbalance and oxidative stress cell death when challenged by nutrient stress. Furthermore, we identify lysosome-mediated cAMP-PKA/EPACdependent activation of the RAF-MEK-ERK pathway to be a novel resistance mechanism that allows NF2 deficient tumor cells to survive YAP/TAZ inhibition in vitro and in vivo. Finally, unbiased analysis of TCGA primary kidney tumor transcriptomes confirms strong correlations of a YAP/TAZ signature with the expression of glycolysis, oxidative phosphorylation and lysosomal genes, validating the clinical relevance of our findings.
2019-05-04 | GSE125408 | GEO
Project description:Integrated ERK-PKA-YAP/TAZ-SHH Signaling Orchestrates Cortical Radial Glia Identity and Lineage Diversification
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Project description:Uncontrolled Transforming growth factor-beta (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce late-stage tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFβ-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFβ, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in non-tumorigenic cells to overcome TGFβ repressive effects. Our work thus identifies crosstalk between nuclear TAZ/YAP and TGFβ signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms. Expression profiling was conducted following the repression of the transcriptional regulators TAZ and YAP (TAZ/YAP), the TEAD family of transcription factors (TEAD1/2/3/4), or the TGFb signaling pathway (with SB-431542, an inhibitor of the TBRI recpeptor) in human MDA-MB-231-LM2 breast cancer cells treated with TGFβ1. Human MDA-MB-231-LM2-4 breast cancer cells were transfected with control siRNA, or siRNAs targeting TAZ/YAP or all four TEADs and were treated 24 hours later with 500pM TGFβ1 or 5mM SB-431542 for an additional 24 hours. Total RNA was isolated and twelve microarrays in total were performed, with each condition carried out three times on separate days. The Boston University Microarray Core generated the data using the Affymetrix Human Gene 1.0 St Array.
2014-04-02 | E-GEOD-56445 | biostudies-arrayexpress
Project description:Organs of all animals reliably grow to a specific size and it is widely thought that such developmental growth control is instructed by the Hippo signaling pathway. This is based on studies in flies and mice showing that deregulation of Hippo signaling causes dramatic tissue overgrowth of various organs. Here we use two major developmental paradigms and provide evidence that removing the key transcriptional downstream effectors of the Hippo pathway does not abolish organ growth control. Specifically, eliminating the function of the Hippo downstream co-activators Yki as well as Yap/Taz that complex with TEAD family transcription factors did not interfere with organ growth control in the developing mouse liver or Drosophila eye. Rather, mutant cells were able to proliferate appropriately during development, properly exit the cell cycle, and form organs of normal size. Remarkably, a complementing whole transcriptome analysis of mutant Drosophila eye imaginal discs corroborated these genetic findings. It showed that loss of the single TEAD transcription factor Scalloped (Sd) fully reverted the effect of overexpression of hyperactivated Yki back to a wildtype gene expression profile. In contrast, Sd/Yap/Taz proved to be crucial for cell survival in injury response models, namely X-ray irradiation of flies and toxic liver injury in mice. Therefore, we propose that Hippo signaling is dispensable for instructing normal organ growth and instead suggest that the classical Hippo mutant overgrowth phenotypes represent a de facto Yap/Taz/Yki gain-of-function situation that does not reflect an endogenous role in growth control. Instead, we hypothesize that the potency of Yap/Taz/Yki to drive tissue overgrowth draws from their broad and primary function in injury responses.
2025-02-28 | GSE96887 | GEO
Project description:In the acute phase of ischemic stroke, endothelial cell (EC) dysfunction leads to breakdown of the blood-brain barrier with increased vascular permeability, vascular inflammation, and transendothelial migration of leukocytes. ECs are also critical for long-term regenerative processes, such as post-stroke angiogenesis, enabling the transition from brain injury to repair. Yes-associated protein 1 (YAP) and WW domain-containing transcriptional regulator 1 (TAZ) are co-transcriptional regulators of EC proliferation and apoptosis. Several studies showed that YAP/TAZ is essential for developmental angiogenesis. However, the role of YAP/TAZ in adult angiogenesis and particularly in experimental stroke is unknown. Here, we subjected mice with an inducible EC-specific deletion of YAP and TAZ (YT-iKO) to 30-min middle cerebral artery occlusion (MCAo) followed by reperfusion to investigate the effects of endothelial YAP/TAZ on acute and long-term outcome after ischemic stroke. First, we examined mRNA expression of genes related to YAP/TAZ signaling in ischemic brain tissue, such as Id1, Smad6, Ankrd and Ccn2. We found a transient induction with highest expression levels acutely after stroke. Surprisingly, endothelial YAP/TAZ deficiency resulted in reduced lesion volumes 28 days after MCAo, whereas acute lesion size 3 days after stroke did not differ. Moreover, Yap/Taz iEC-KO animals showed no gross differences in vessels morphology 28 days after stroke, and no effect was detected on blood vessel density and EC density. We therefore speculated whether angiogenesis-independent effects of YAP/TAZ might also be associated with improved long-term outcome after stroke. To better understand the underlying mechanisms, we performed RNA sequencing of ECs isolated from ischemic brain tissue of YT-iKO compared with CTRL animals 72h post stroke. Here, we identified differently expressed gene sets involved in inflammatory responses. Therefore, we studied the non-endothelial tissue environment of the brain. We found, that EC YAP/TAZ deletion led to increased expression of anti-inflammatory genes accompanied by increased infiltration of myeloid cells, suggesting a protective phenotype. Besides, acute microglia proliferation was reduced in Y/T-iKO animals. Overall, our results provide new insights into the role of endothelial YAP/TAZ in neuroinflammation after cerebral ischemia. YAP/TAZ may therefore be a potential therapeutic target for the treatment of ischemic stroke.
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Project description:Pancreas volume or mass varies more than 3-fold among adult humans. The heterogeneity is likely the result of genetics, diseases, and nutrition. Dietary protein intake and blood amino acid levels are known to affect pancreas mass, but the underlying mechanism is not well understood. The goal of this study is to determine how increased blood amino acid level (hyperaminoacidemia) induces pancreas expansion.Multiple complementary mouse and zebrafish models were used to study the impact of hyperaminoacidemia on pancreatic mass, acinar cell size and proliferation. Blood amino acid levels were manipulated by dietary protein content, or by pharmacologic or genetic interruption of glucagon signaling (IGS). The activation of mammalian target of rapamycin complex 1 (mTORC1) and Yes-associated protein 1 (YAP) were determined by pS6 and YAP staining. Sirolimus administration in mice and knockdown of solute carrier family 38 member 5b (slc38a5b) and yap/taz in zebrafish were used to determine the role of mTORC1, SLC38A5 and YAP/TAZ in acinar cell proliferation and pancreas expansion. We found that the IGS-induced pancreas expansion was the result of acinar cell proliferation and hypertrophy. Hyperaminoacidemia was the likely mediator as pancreas expansion was blunted by a low protein diet in mice and by knocking down the most highly expressed amino acid transporter gene, slc38a5b, in zebrafish lacking both glucagon receptor genes (gcgr-/-). In GCGR-Ab treated mice, inhibition of mTORC1 attenuated both hyperplasia and hypertrophy of acinar cells. There was a gene expression signature of YAP activation in acinar cells, consistent with increased YAP-expressing acinar cells in GCGR-Ab treated mice and increased fraction of acinar cells with nuclear YAP1 in gcgr-/- zebrafish. Knocking down yap1 or taz decreased mTORC1 activity and acinar cell hyperplasia and hypertrophy in gcgr-/- zebrafish. Hyperaminoacidemia leads to acinar cell proliferation and hypertrophy via activation of both mTORC1 and YAP pathways. The study discovered a previously unrecognized role of the YAP/Taz pathway in hyperaminoacidemia-induced acinar cell hypertrophy and hyperplasia.
2024-03-30 | GSE243695 | GEO
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
Project description:We conditionally knocked out both Yap and Taz in cranial neural crest (CNC) using the Wnt1Cre driver and sequenced mRNA from embryonic day 10.5 mandibles. Examination of mRNA level in E10.5 mandibular tissues from control and Wnt1Cre Taz and Yap dKO mutant.
2016-03-01 | E-GEOD-69311 | biostudies-arrayexpress