A High-Resolution Anatomical Atlas of the Transcriptome in the Mouse Embryo

Diez‐Roux, Graciana; Banfi, Sandro; Sultan, Marc; Geffers, Lars; Anand, Santosh; Rozado, David; Magen, Alon; Canidio, Elena; Pagani, Massimiliano; Peluso, Ilaria; Lin-Marq, Nathalie; Koch, Marc; Bilio, Marchesa; Cantiello, Immacolata; Verde, Roberta; Masi, Cristian De; Bianchi, Salvatore; Cicchini, Juliette; Perroud, Elodie; Mehmeti, Shprese; Dagand, Emilie; Schrinner, Sabine; Nürnberger, Asja; Schmidt, Katja; Metz, Katja; Zwingmann, Christina; Brieske, Norbert; Springer, Cindy; Hernandez, Ana Martinez; Herzog, Sarah; Grabbe, Frauke; Sieverding, Cornelia; Fischer, Barbara; Schrader, Kathrin; Brockmeyer, Maren; Dettmer, Sarah; Helbig, Christin; Alunni, Violaine; Battaini, Marie-Annick; Mura, Carole; Henrichsen, Charlotte N.; García-López, Raquel; Echevarrı́a, Diego; Puelles, Eduardo; Garcı́a-Calero, Elena; Kruse, Stefan; Uhr, M.; Kauck, Christine; Feng, Guangjie; Milyaev, Nestor; Ong, Chuang Kee; Kumar, Lalit; Lam, MeiSze; Semple, Colin A.; Gyenesei, Attila; Mundlos, Stefan; Radelof, Uwe; Lehrach, Hans; Sarmientos, Paolo; Reymond, Alexandre; Davidson, Duncan; Dollé, Pascal; Antonarakis, Stylianos E.; Yaspo, Marie–Laure; Martı́nez, Salvador; Baldock, Richard; Eichele, Gregor; Ballabio, Andrea

doi:10.1371/journal.pbio.1000582

Cited by 569 publications

(577 citation statements)

References 41 publications

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“…At the same time, it is noteworthy that Fbxl17 transcription is blocked by methylation in embryonic stem cells and transcribed in neural stem cells where Hh plays a more active role (Cortese et al , 2011). In line with this, Fbxl17 expression is increased in the brain and spinal cord during development (Diez‐Roux et al , 2011), pointing out to a role for Fbxl17 in physiological development. Furthermore, a putative homolog of Fbxl17 (CG31633) has been described in D. melanogaster , where the absence of the latter induces a pupal lethal phenotype (Dui et al , 2012), suggesting an essential role of Fbxl17 in development.…”

Section: Discussionmentioning

confidence: 72%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

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Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma.

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Section: Discussionmentioning

confidence: 72%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

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“…The BAC transgene also confirmed an earlier result with a very similar BAC construct, showing that replacing the first exon of Fto with a lacZ cassette recapitulated the endogenous Fto expression pattern (Smemo et al ., 2014). In the mouse embryo, Fto displays near ubiquitous expression, while Irx3 is specifically expressed in several brain regions (Diez‐Roux et al, 2011). …”

Section: Resultsmentioning

confidence: 99%

BAC transgenic zebrafish reveal hypothalamic enhancer activity around obesity associated SNP rs9939609 within the human FTO gene

Rinkwitz

Geng

Manning

et al. 2015

Genesis

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SummarySingle Nucleotide Polymorphisms in FTO intron 1 have been associated with obesity risk, leading to the hypothesis that FTO is the obesity‐related gene. However, other studies have shown that the FTO gene is part of the regulatory domain of the neighboring IRX3 gene and that enhancers in FTO intron 1 regulate IRX3. While Irx3 activity was shown to be necessary in the hypothalamus for the metabolic function of Irx3 in mouse, no enhancers with hypothalamic activity have been demonstrated in the risk‐associated region within FTO. In order to identify potential enhancers at the human FTO locus in vivo, we tested regulatory activity in FTO intron 1 using BAC transgenesis in zebrafish. A minimal gata2 promoter‐GFP cassette was inserted 1.3 kb upstream of the obesity associated SNP rs9939609 in a human FTO BAC plasmid. In addition to the previously identified expression domains in notochord and kidney, human FTO BAC:GFP transgenic zebrafish larvae expressed GFP in the ventral posterior tuberculum, the posterior hypothalamus and the anterior brainstem, which are also expression domains of zebrafish irx3a. In contrast, an in‐frame insertion of a GFP cassette at the FTO start codon resulted in weak ubiquitous GFP expression indicating that the promoter of FTO does likely not react to enhancers located in the obesity risk‐associated region. genesis 53:640–651, 2015. © 2015 The Authors. genesis Published by Wiley Periodicals, Inc.

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“…For instance, Fry has been shown to be essential for the organization of Drosophila sensory neuronal dendrites to cover the entire receptive field without redundancy by avoiding homologous dendritic branches (25). Although Fry expression has been demonstrated in embryonic mammalian brain tissue (85), the role of Fry in mammalian systems has not been studied. Teneurins are required for transsynaptic signaling and organization of the synapse cytoskeleton in Drosophila neuromuscular synapses and olfactory receptor neurons (33,86).…”

Section: Discussionmentioning

confidence: 99%

In vivo quantitative proteomics of somatosensory cortical synapses shows which protein levels are modulated by sensory deprivation

Butko¹,

Savas

Friedman³

et al. 2013

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

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Postnatal bilateral whisker trimming was used as a model system to test how synaptic proteomes are altered in barrel cortex by sensory deprivation during synaptogenesis. Using quantitative mass spectrometry, we quantified more than 7,000 synaptic proteins and identified 89 significantly reduced and 161 significantly elevated proteins in sensory-deprived synapses, 22 of which were validated by immunoblotting. More than 95% of quantified proteins, including abundant synaptic proteins such as PSD-95 and gephyrin, exhibited no significant difference under high-and low-activity rearing conditions, suggesting no tissue-wide changes in excitatory or inhibitory synaptic density. In contrast, several proteins that promote mature spine morphology and synaptic strength, such as excitatory glutamate receptors and known accessory factors, were reduced significantly in deprived synapses. Immunohistochemistry revealed that the reduction in SynGAP1, a postsynaptic scaffolding protein, was restricted largely to layer I of barrel cortex in sensorydeprived rats. In addition, protein-degradation machinery such as proteasome subunits, E2 ligases, and E3 ligases, accumulated significantly in deprived synapses, suggesting targeted synaptic protein degradation under sensory deprivation. Importantly, this screen identified synaptic proteins whose levels were affected by sensory deprivation but whose synaptic roles have not yet been characterized in mammalian neurons. These data demonstrate the feasibility of defining synaptic proteomes under different sensory rearing conditions and could be applied to elucidate further molecular mechanisms of sensory development. mass spectrometric proteomics | somatosensory cortex | experience-dependent plasticity | synaptic protein dynamics S ensory information is encoded in the brain by activation of specific neuronal circuits that operate via chemical synapses. Important sensory experiences are stored by strengthening activated synapses in the circuit, a process known as "experience-dependent plasticity" (1). When animals are deprived of sensory experience during development, for example, by trimming rodent whiskers from birth to 30 d after birth, synaptic strength and mature synaptic morphology are attenuated, suggesting that the low activity in the deprived circuits interferes with normal development (2-7). However, the molecular changes that alter these synaptic properties in response to experience remain unclear. Synaptic activation has been shown to promote regulated and highly localized effects on synaptic proteins such as local translation, recruitment, and targeted degradation (8-11), and this spatiotemporal control of protein availability is required for long-term plasticity and synaptic maturation, which are fundamental in memory formation and storage and ultimately for an organism's survival (12-14). The need for highly controlled protein availability is highlighted in studies of neurological diseases, which often result from the disruption of protein availability at the synapse (15-17). ...

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A High-Resolution Anatomical Atlas of the Transcriptome in the Mouse Embryo

Abstract: The manuscript describes the “digital transcriptome atlas” of the developing mouse embryo, a powerful resource to determine co-expression of genes, to identify cell populations and lineages and to identify functional associations between genes relevant to development and disease.

Cited by 569 publications

References 41 publications

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

BAC transgenic zebrafish reveal hypothalamic enhancer activity around obesity associated SNP rs9939609 within the human FTO gene

In vivo quantitative proteomics of somatosensory cortical synapses shows which protein levels are modulated by sensory deprivation

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