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Alexandra L Joyner - One of the best experts on this subject based on the ideXlab platform.
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titration of GLI3 repressor activity by sonic hedgehog signaling is critical for maintaining multiple adult neural stem cell and astrocyte functions
The Journal of Neuroscience, 2013Co-Authors: Ralitsa Petrova, Alexandra L Joyner, A D R GarciaAbstract:Sonic hedgehog (SHH), a key regulator of embryonic neurogenesis, signals directly to neural stem cells (NSCs) in the subventricular zone (SVZ) and to astrocytes in the adult mouse forebrain. The specific mechanism by which the GLI2 and GLI3 transcriptional activators (GLI2A and GLI3A) and repressors (GLI2R and GLI3R) carry out SHH signaling has not been addressed. We found that the majority of slow-cycling NSCs express Gli2 and GLI3, whereas Gli1 is restricted ventrally and all three genes are downregulated when NSCs transition into proliferating progenitors. Surprisingly, whereas conditional ablation of Smo in postnatal glial fibrillary acidic protein-expressing cells results in cell-autonomous loss of NSCs and a progressive reduction in SVZ proliferation, without an increase in glial cell production, removal of Gli2 or GLI3 does not alter adult SVZ neurogenesis. Significantly, removing GLI3 in Smo conditional mutants largely rescues neurogenesis and, conversely, expression of a constitutive GLI3R in the absence of normal Gli2 and GLI3 abrogates neurogenesis. Thus unattenuated GLI3R is a primary inhibitor of adult SVZ NSC function. Ablation of Gli2 and GLI3 revealed a minor role for GLI2R and little requirement for GLIA function in stimulating SVZ neurogenesis. Moreover, we found that similar rules of GLI activity apply to SHH signaling in regulating SVZ-derived olfactory bulb interneurons and maintaining cortical astrocyte function. Namely, fewer superficial olfactory bulb interneurons are generated in the absence of Gli2 and GLI3, whereas astrocyte partial gliosis results from an increase in GLI3R. Thus precise titration of GLIR levels by SHH is critical to multiple functions of adult NSCs and astrocytes.
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limb anterior posterior polarity integrates activator and repressor functions of gli2 as well as GLI3
Developmental Biology, 2012Co-Authors: Megan Bowers, Liane Eng, Zhimin Lao, Rowena Turnbull, Xiaozhong Bao, Elyn Riedel, Susan Mackem, Alexandra L JoynerAbstract:Anterior-posterior (AP) limb patterning is directed by sonic hedgehog (SHH) signaling from the posteriorly located zone of polarizing activity (ZPA). GLI3 and GLI2 are the transcriptional mediators generally utilized in SHH signaling, and each can function as an activator (A) and repressor (R). Although GLI3R has been suggested to be the primary effector of SHH signaling during limb AP patterning, a role for GLI3A or GLI2 has not been fully ruled out, nor has it been determined whether GLI3 plays distinct roles in limb development at different stages. By conditionally removing GLI3 in the limb at multiple different time points, we uncovered four GLI3-mediated functions in limb development that occur at distinct but partially over-lapping time windows: AP patterning of the proximal limb, AP patterning of the distal limb, regulation of digit number and bone differentiation. Furthermore, by removing Gli2 in GLI3 temporal conditional knock-outs, we uncovered an essential role for Gli2 in providing the remaining posterior limb patterning seen in GLI3 single mutants. To test whether GLIAs or GLIRs regulate different aspects of AP limb patterning and/or digit number, we utilized a knock-in allele in which GLI1, which functions solely as an activator, is expressed in place of the bifunctional GLI2 protein. Interestingly, we found that GLIAs contribute to AP patterning specifically in the posterior limb, whereas GLIRs predominantly regulate anterior patterning and digit number. Since GLI3 is a more effective repressor, our results explain why GLI3 is required only for anterior limb patterning and why GLI2 can compensate for GLI3A in posterior limb patterning. Taken together, our data suggest that establishment of a complete range of AP positional identities in the limb requires integration of the spatial distribution, timing, and dosage of GLI2 and GLI3 activators and repressors.
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spatial pattern of sonic hedgehog signaling through gli genes during cerebellum development
Development, 2004Co-Authors: Jomichelle D Corrales, Gina L Rocco, Sandra Blaess, Alexandra L JoynerAbstract:The cerebellum consists of a highly organized set of folia that are largely generated postnatally during expansion of the granule cell precursor (GCP) pool. Since the secreted factor sonic hedgehog (Shh) is expressed in Purkinje cells and functions as a GCP mitogen in vitro, it is possible that Shh influences foliation during cerebellum development by regulating the position and/or size of lobes. We studied how Shh and its transcriptional mediators, the Gli proteins, regulate GCP proliferation in vivo, and tested whether they influence foliation. We demonstrate that Shh expression correlates spatially and temporally with foliation. Expression of the Shh target gene Gli1 is also highest in the anterior medial cerebellum, but is restricted to proliferating GCPs and Bergmann glia. By contrast, Gli2 is expressed uniformly in all cells in the developing cerebellum except Purkinje cells and GLI3 is broadly expressed along the anteroposterior axis. Whereas Gli mutants have a normal cerebellum, Gli2 mutants have greatly reduced foliation at birth and a decrease in GCPs. In a complementary study using transgenic mice, we show that overexpressing Shh in the normal domain does not grossly alter the basic foliation pattern, but does lead to prolonged proliferation of GCPs and an increase in the overall size of the cerebellum. Taken together, these studies demonstrate that positive Shh signaling through Gli2 is required to generate a sufficient number of GCPs for proper lobe growth.
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all mouse ventral spinal cord patterning by hedgehog is gli dependent and involves an activator function of GLI3
Developmental Cell, 2004Co-Authors: Brian C Bai, Alexandra L Joyner, Daniel StephenAbstract:An important question is how the gradient of Hedgehog is interpreted by cells at the level of the Gli transcription factors. The full range of Gli activity and its dependence on Hh have not been determined, although the Gli2 activator and GLI3 repressor have been implicated. Using the spinal cord as a model system, we demonstrate that GLI3 can transduce Hedgehog signaling as an activator. All expression of the Hh target gene Gli1 is dependent on both Gli2 and GLI3. Unlike Gli2, however, GLI3 requires endogenous Gli1 for induction of floor plate and V3 interneurons. Strikingly, embryos lacking all Gli function develop motor neurons and three ventral interneuron subtypes, similar to embryos lacking Hh signaling and GLI3. Therefore, in the spinal cord all Hh signaling is Gli dependent. Furthermore, a combination of Gli2 and GLI3 is required to regulate motor neuron development and spatial patterning of ventral spinal cord progenitors.
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specific and redundant functions of gli2 and GLI3 zinc finger genes in skeletal patterning and development
Development, 1997Co-Authors: A M Freer, D L Zinyk, Michael A Crackower, J Michaud, Henry H Q Heng, Ki Wai Chik, X M Shi, Lapchee Tsui, Shuk Han Cheng, Alexandra L JoynerAbstract:The correct patterning of vertebrate skeletal elements is controlled by inductive interactions. Two vertebrate hedgehog proteins, Sonic hedgehog and Indian hedgehog, have been implicated in skeletal development. During somite differentiation and limb development, Sonic hedgehog functions as an inductive signal from the notochord, floor plate and zone of polarizing activity. Later in skeletogenesis, Indian hedgehog functions as a regulator of chondrogenesis during endochondral ossification. The vertebrate Gli zinc finger proteins are putative transcription factors that respond to Hedgehog signaling. In Drosophila, the Gli homolog cubitus interruptus is required for the activation of hedgehog targets and also functions as a repressor of hedgehog expression. We show here that Gli2 mutant mice exhibit severe skeletal abnormalities including cleft palate, tooth defects, absence of vertebral body and intervertebral discs, and shortened limbs and sternum. Interestingly, Gli2 and GLI3 (C.-c. Hui and A. L. Joyner (1993). Nature Genet. 3, 241–246) mutant mice exhibit different subsets of skeletal defects indicating that they implement specific functions in the development of the neural crest, somite and lateral plate mesoderm derivatives. Although Gli2 and GLI3 are not functionally equivalent, double mutant analysis indicates that, in addition to their specific roles, they also serve redundant functions during skeletal development. The role of Gli2 and GLI3 in Hedgehog signaling during skeletal development is discussed.
Chichung Hui - One of the best experts on this subject based on the ideXlab platform.
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a genetic female mouse model with congenital genitourinary anomalies and adult stages of urinary incontinence
Neurourology and Urodynamics, 2017Co-Authors: Pedram Akbari, Chichung Hui, Ali Fathollahi, Michael Kavran, Nicole Episalla, Walid A Farhat, Adonis HijazAbstract:AIMS To characterize the urinary incontinence observed in adult Gli2+/- ; GLI3Δ699/+ female mice and identify the defects underlying the condition. METHODS Gli2+/- and GLI3Δ699/+ mice were crossed to generate: wild-type, mutant Gli2 (Gli2+/- ), mutant GLI3 (GLI3Δ699/+ ), and double mutant (Gli2+/- ; GLI3Δ699/+ ) female mice, verified via Polymerase Chain Reactions. Bladder functional studies including cystometrogram (CMG), leak point pressure (LPP), and voiding testing were performed on adult female mice. Female bladders and urethras were also analyzed via ink injection and histological assays. RESULTS CMG tracing showed no signal corresponding to the filling of the Gli2+/- ; GLI3Δ699/+ bladders. LPP were significantly reduced in Gli2+/- ; GLI3Δ699/+ mice compared to wild-type mice. CMG studies revealed a decrease in peak micturition pressure values in Gli2+/- ; GLI3Δ699/+ mice compared with all other groups. No significant differences between mutant and wild-type mice were detected in urinary output. Histological analyses revealed Gli2+/- ; GLI3Δ699/+ mice exhibited a widened urethra and a decrease in smooth muscle layer thickness in the bladder outlet and urethra, with increased mucosal folding. CONCLUSIONS Gli2+/- ; GLI3Δ699/+ adult female mice display persistent urinary incontinence due to the malformation of the bladder outlet and urethra. This presents a consistent and reliable genetic mouse model for female urinary incontinence and alludes to the key role of genetic factors involved in the condition.
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Gli2 and GLI3 play distinct roles in the dorsoventral patterning of the mouse hindbrain
Developmental biology, 2006Co-Authors: Mélanie Lebel, Kenji Shimamura, Chichung HuiAbstract:Abstract Sonic Hedgehog (Shh) signaling plays a critical role during dorsoventral (DV) patterning of the developing neural tube by modulating the expression of neural patterning genes. Overlapping activator functions of Gli2 and GLI3 have been shown to be required for motoneuron development and correct neural patterning in the ventral spinal cord. However, the role of Gli2 and GLI3 in ventral hindbrain development is unclear. In this paper, we have examined DV patterning of the hindbrain of Shh−/−, Gli2−/− and GLI3−/− embryos, and found that the respective role of Gli2 and GLI3 is not only different between the hindbrain and spinal cord, but also at distinct rostrocaudal levels of the hindbrain. Remarkably, the anterior hindbrain of Gli2−/− embryos displays ventral patterning defects as severe as those observed in Shh−/− embryos suggesting that, unlike in the spinal cord and posterior hindbrain, GLI3 cannot compensate for the loss of Gli2 activator function in Shh-dependent ventral patterning of the anterior hindbrain. Loss of GLI3 also results in a distinct patterning defect in the anterior hindbrain, including dorsal expansion of Nkx6.1 expression. Furthermore, we demonstrate that ventral patterning of rhombomere 4 is less affected by loss of Gli2 function revealing a different requirement for Gli proteins in this rhombomere. Taken together, these observations indicate that Gli2 and GLI3 perform rhombomere-specific function during DV patterning of the hindbrain.
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GLI3 dependent transcriptional repression of gli1 gli2 and kidney patterning genes disrupts renal morphogenesis
Development, 2006Co-Authors: Sita Bhella, Chichung Hui, Christopher W Wilson, Paotien Chuang, Norman D RosenblumAbstract:Truncating mutations in GLI3 , an intracellular effector in the SHH-SMO-GLI signaling pathway, cause renal aplasia/dysplasia in humans and mice. Yet, the pathogenic mechanisms are undefined. Here, we report the effect of decreased SHH-SMO signaling on renal morphogenesis, the expression of SHH target genes and GLI binding to Shh target genes. Shh deficiency or cyclopamine-mediated SMO inhibition disrupted renal organogenesis, decreased expression of GLI1 and GLI2 proteins, but increased expression of GLI3 repressor relative to GLI3 activator. Shh deficiency decreased expression of kidney patterning genes ( Pax2 and Sall1 ) and cell cycle regulators (cyclin D1 and MYCN). Elimination of GLI3 in Shh–/– mice rescued kidney malformation and restored expression of Pax2, Sall1 , cyclin D1, MYCN, Gli1 and Gli2 . To define mechanisms by which SHH-SMO signaling controls gene expression, we determined the binding of GLI proteins to 5′ flanking regions containing GLI consensus binding sequences in Shh target genes using chromatin immunoprecipitation. In normal embryonic kidney tissue, GLI1 and/or GLI2 were bound to each target gene. By contrast, treatment of embryonic kidney explants with cyclopamine decreased GLI1 and/or GLI2 binding, and induced binding of GLI3. However, cyclopamine failed to decrease Gli1 and Gli2 expression and branching morphogenesis in GLI3 -deficient embryonic kidney tissue. Together, these results demonstrate that SHH-SMO signaling controls renal morphogenesis via transcriptional control of Gli , renal patterning and cell cycle regulator genes in a manner that is opposed by GLI3.
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gli2 and GLI3 have redundant and context dependent function in skeletal muscle formation
Development, 2005Co-Authors: Aileen Mcdermott, Charles P Emerson, Chichung Hui, Marcus K Gustafsson, Thomas Elsam, Anne-gaëlle BoryckiAbstract:The Gli family of zinc finger transcription factors are mediators of Shh signalling in vertebrates. In previous studies, we showed that Shh signalling, via an essential Gli -binding site in the Myf5 epaxial somite (ES) enhancer, is required for the specification of epaxial muscle progenitor cells. Shh signalling is also required for the normal mediolateral patterning of myogenic cells within the somite. In this study, we investigate the role and the transcriptional activities of Gli proteins during somite myogenesis in the mouse embryo. We report that Gli genes are differentially expressed in the mouse somite. Gli2 and GLI3 are essential for Gli1 expression in somites, establishing Gli2 and GLI3 as primary mediators and Gli1 as a secondary mediator of Shh signalling. Combining genetic studies with the use of a transgenic mouse line expressing a reporter gene under the control of the Myf5 epaxial somite enhancer, we show that Gli2 or GLI3 is required for Myf5 activation in the epaxial muscle progenitor cells. Furthermore, GLI3, but not Gli2 represses Myf5 transcription in a dose-dependent manner in the absence of Shh. Finally, we provide evidence that hypaxial and myotomal gene expression is mispatterned in Gli2–/–GLI3–/– and GLI3–/–Shh–/– somites. Together, our data demonstrate both positive and negative regulatory functions for Gli2 and GLI3 in the control of Myf5 activation in the epaxial muscle progenitor cells and in dorsoventral and mediolateral patterning of the somite.
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Interplays of Gli2 and GLI3 and their requirement in mediating Shh-dependent sclerotome induction.
Development (Cambridge England), 2003Co-Authors: Laura Buttitta, Chichung Hui, Chen-ming FanAbstract:Sonic hedgehog (Shh) signaling is essential for sclerotome development in the mouse. Gli2 and GLI3 are thought to be the primary transcriptional mediators of Shh signaling; however, their roles in Shh induction of sclerotomal genes have not been investigated. Using a combination of mutant analysis and in vitro explant assays, we demonstrate that Gli2 and GLI3 are required for Shh-dependent sclerotome induction. Gli2 –/– GLI3 –/– embryos exhibit a severe loss of sclerotomal gene expression, and somitic mesoderm from these embryos cannot activate sclerotomal genes in response to exogenous Shh. We find that one copy of either Gli2 or GLI3 is required to mediate Shh induction of sclerotomal markers Pax1 and Pax9 in vivo and in vitro. Although Gli2 is generally considered an activator and GLI3 a repressor, our results also reveal a repressor function for Gli2 and an activator function for GLI3 in the developing somite. To further dissect the function of each Gli, we used adenovirus to overexpress Gli1, Gli2 and GLI3 in presomitic mesoderm explants. We find that each Gli preferentially activates a distinct set of Shh target genes, suggesting that the functions of Shh in patterning, growth and negative feedback are divided preferentially between different Gli proteins in the somite.
Ruiz A I Altaba - One of the best experts on this subject based on the ideXlab platform.
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expression of the vertebrate gli proteins in drosophila reveals a distribution of activator and repressor activities
Development, 2000Co-Authors: Pedro Azablanc, Ruiz A I Altaba, Thomas B KornbergAbstract:The Cubitus interruptus (Ci) and Gli proteins are transcription factors that mediate responses to Hedgehog proteins (Hh) in flies and vertebrates, respectively. During development of the Drosophila wing, Ci transduces the Hh signal and regulates transcription of different target genes at different locations. In vertebrates, the three Gli proteins are expressed in overlapping domains and are partially redundant. To assess how the vertebrate Glis correlate with Drosophila Ci, we expressed each in Drosophila and monitored their behaviors and activities. We found that each Gli has distinct activities that are equivalent to portions of the regulatory arsenal of Ci. Gli2 and Gli1 have activator functions that depend on Hh. Gli2 and GLI3 are proteolyzed to produce a repressor form able to inhibit hh expression. However, while GLI3 repressor activity is regulated by Hh, Gli2 repressor activity is not. These observations suggest that the separate activator and repressor functions of Ci are unevenly partitioned among the three Glis, yielding proteins with related yet distinct properties.
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gli proteins encode context dependent positive and negative functions implications for development and disease
Development, 1999Co-Authors: Ruiz A I AltabaAbstract:Several lines of evidence implicate zinc finger proteins of the Gli family in the final steps of Hedgehog signaling in normal development and disease. C-terminally truncated mutant GLI3 proteins are also associated with human syndromes, but it is not clear whether these C-terminally truncated Gli proteins fulfil the same function as full-length ones. Here, structure-function analyses of Gli proteins have been performed using floor plate and neuronal induction assays in frog embryos, as well as induction of alkaline phosphatase (AP) in SHH-responsive mouse C3H10T1/2 (10T1/2) cells. These assays show that C-terminal sequences are required for positive inducing activity and cytoplasmic localization, whereas N-terminal sequences determine dominant negative function and nuclear localization. Analyses of nuclear targeted Gli1 and Gli2 proteins suggest that both activator and dominant negative proteins are modified forms. In embryos and COS cells, tagged Gli cDNAs yield C-terminally deleted forms similar to that of Ci. These results thus provide a molecular basis for the human Polydactyly type A and Pallister-Hall Syndrome phenotypes, derived from the deregulated production of C-terminally truncated GLI3 proteins. Analyses of full-length Gli function in 10T1/2 cells suggest that nuclear localization of activating forms is a regulated event and show that only Gli1 mimics SHH in inducing AP activity. Moreover, full-length GLI3 and all C-terminally truncated forms act antagonistically whereas Gli2 is inactive in this assay. In 10T1/2 cells, protein kinase A (PKA), a known inhibitor of Hh signaling, promotes GLI3 repressor formation and inhibits Gli1 function. Together, these findings suggest a context-dependent functional divergence of Gli protein function, in which a cell represses GLI3 and activates Gli1/2 prevents the formation of repressor Gli forms to respond to Shh. Interpretation of Hh signals by Gli proteins therefore appears to involve a fine balance of divergent functions within each and among different Gli proteins, the misregulation of which has profound biological consequences.
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combinatorial gli gene function in floor plate and neuronal inductions by sonic hedgehog
Development, 1998Co-Authors: Ruiz A I AltabaAbstract:Within the developing vertebrate nervous system, it is not known how progenitor cells interpret the positional information provided by inducing signals or how the domains in which distinct groups of neural cells differentiate are defined. Gli proteins may be involved in these processes. In the frog neural plate, we have previously shown that the zinc finger transcription factor Gli1 is expressed in midline cells and mediates the effects of Shh inducing floor plate differentiation. In contrast, Gli2 and GLI3 are expressed throughout the neural plate except for the midline. Here, it is shown that GLI3 and Shh repress each other whereas Gli2, like Gli1, is a target of Shh signaling. However, only Gli1 can induce the differentiation of floor plate cells. In addition, Gli2 and GLI3 repress the ectopic induction of floor plate cells by Gli1 in co-injection assays and inhibit endogenous floor plate differentiation. The definition of the floor plate domain, therefore, appears to be defined by the antagonizing activities of Gli2 and GLI3 on Gli1 function. Because both Gli1 and Gli2 are induced by Shh, these results establish a regulatory feedback loop triggered by Shh that restricts floor plate cells to the midline. We have also previously shown that the Gli genes induce neuronal differentiation and here it is shown that there is specificity to the types of neurons the Gli proteins induce. Only Gli1 induces Nkx2.1/TTF-1(+) ventral forebrain neurons. Moreover, Gli2 and GLI3 inhibit their differentiation. In contrast, the differentiation of spinal motor neurons can be induced by the two ventrally expressed Gli genes, Gli1 and Gli2, suggesting that Gli2 directly mediates induction of motor neurons by Shh. In addition, GLI3 inhibits motor neuron differentiation by Gli2. Thus, combinatorial Gli function may pattern the neural tube, integrating positional information and cell type differentiation.
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gli1 is a target of sonic hedgehog that induces ventral neural tube development
Development, 1997Co-Authors: K A Platt, P Censullo, Ruiz A I AltabaAbstract:The vertebrate zinc finger genes of the Gli family are homologs of the Drosophila gene cubitus interruptus. In frog embryos, Gli1 is expressed transiently in the prospective floor plate during gastrulation and in cells lateral to the midline during late gastrula and neurula stages. In contrast, Gli2 and GLI3 are absent from the neural plate midline with Gli2 expressed widely and GLI3 in a graded fashion with highest levels in lateral regions. In mouse embryos, the three Gli genes show a similar pattern of expression in the neural tube but are coexpressed throughout the early neural plate. Because Gli1 is the only Gli gene expressed in prospective floor plate cells of frog embryos, we have investigated a possible involvement of this gene in ventral neural tube development. Here we show that Shh signaling activates Gli1 transcription and that widespread expression of endogenous frog or human glioma Gli1, but not GLI3, in developing frog embryos results in the ectopic differentiation of floor plate cells and ventral neurons within the neural tube. Floor-plate-inducing ability is retained when cytoplasmic Gli1 proteins are forced into the nucleus or are fused to the VP16 transactivating domain. Thus, our results identify Gli1 as a midline target of Shh and suggest that it mediates the induction of floor plate cells and ventral neurons by Shh acting as a transcriptional regulator.
Yoshihiro Tsukamoto - One of the best experts on this subject based on the ideXlab platform.
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GLI3 Is Associated With Neuronal Differentiation in SHH-Activated and WNT-Activated Medulloblastoma.
Journal of neuropathology and experimental neurology, 2020Co-Authors: Manabu Natsumeda, Hiroaki Miyahara, Junichi Yoshimura, Satoshi Nakata, Takanori Nozawa, Junko Ito, Yu Kanemaru, Jun Watanabe, Yoshihiro Tsukamoto, Masayasu OkadaAbstract:Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.
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GLI3 is associated with neuronal differentiation in shh activated and wnt activated medulloblastoma
Journal of Neuropathology and Experimental Neurology, 2020Co-Authors: Manabu Natsumeda, Hiroaki Miyahara, Junichi Yoshimura, Satoshi Nakata, Takanori Nozawa, Junko Ito, Yu Kanemaru, Jun Watanabe, Yoshihiro TsukamotoAbstract:Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.
Hiroaki Miyahara - One of the best experts on this subject based on the ideXlab platform.
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GLI3 Is Associated With Neuronal Differentiation in SHH-Activated and WNT-Activated Medulloblastoma.
Journal of neuropathology and experimental neurology, 2020Co-Authors: Manabu Natsumeda, Hiroaki Miyahara, Junichi Yoshimura, Satoshi Nakata, Takanori Nozawa, Junko Ito, Yu Kanemaru, Jun Watanabe, Yoshihiro Tsukamoto, Masayasu OkadaAbstract:Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.
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GLI3 is associated with neuronal differentiation in shh activated and wnt activated medulloblastoma
Journal of Neuropathology and Experimental Neurology, 2020Co-Authors: Manabu Natsumeda, Hiroaki Miyahara, Junichi Yoshimura, Satoshi Nakata, Takanori Nozawa, Junko Ito, Yu Kanemaru, Jun Watanabe, Yoshihiro TsukamotoAbstract:Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.