Publications by authors named "Lucille Lopez-Delisle"

17 Publications

  • Page 1 of 1

Mesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations.

Nat Commun 2021 08 18;12(1):5013. Epub 2021 Aug 18.

School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

Human families with chromosomal rearrangements at 2q31, where the human HOXD locus maps, display mesomelic dysplasia, a severe shortening and bending of the limb. In mice, the dominant Ulnaless inversion of the HoxD cluster produces a similar phenotype suggesting the same origin for these malformations in humans and mice. Here we engineer 1 Mb inversion including the HoxD gene cluster, which positioned Hoxd13 close to proximal limb enhancers. Using this model, we show that these enhancers contact and activate Hoxd13 in proximal cells, inducing the formation of mesomelic dysplasia. We show that a secondary Hoxd13 null mutation in-cis with the inversion completely rescues the alterations, demonstrating that ectopic HOXD13 is directly responsible for this bone anomaly. Single-cell expression analysis and evaluation of HOXD13 binding sites suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.
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http://dx.doi.org/10.1038/s41467-021-25330-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373931PMC
August 2021

Induction of a chromatin boundary in vivo upon insertion of a TAD border.

PLoS Genet 2021 Jul 22;17(7):e1009691. Epub 2021 Jul 22.

Department of Genetics and Evolution, Faculty of Science, University of Geneva, Geneva, Switzerland.

Mammalian genomes are partitioned into sub-megabase to megabase-sized units of preferential interactions called topologically associating domains or TADs, which are likely important for the proper implementation of gene regulatory processes. These domains provide structural scaffolds for distant cis regulatory elements to interact with their target genes within the three-dimensional nuclear space and architectural proteins such as CTCF as well as the cohesin complex participate in the formation of the boundaries between them. However, the importance of the genomic context in providing a given DNA sequence the capacity to act as a boundary element remains to be fully investigated. To address this question, we randomly relocated a topological boundary functionally associated with the mouse HoxD gene cluster and show that it can indeed act similarly outside its initial genomic context. In particular, the relocated DNA segment recruited the required architectural proteins and induced a significant depletion of contacts between genomic regions located across the integration site. The host chromatin landscape was re-organized, with the splitting of the TAD wherein the boundary had integrated. These results provide evidence that topological boundaries can function independently of their site of origin, under physiological conditions during mouse development.
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http://dx.doi.org/10.1371/journal.pgen.1009691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330945PMC
July 2021

Time-sequenced transcriptomes of developing distal mouse limb buds: A comparative tissue layer analysis.

Dev Dyn 2021 Jul 12. Epub 2021 Jul 12.

Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (CSIC-University of Cantabria-SODERCAN), Santander, Spain.

Background: The development of the amniote limb has been an important model system to study patterning mechanisms and morphogenesis. For proper growth and patterning, it requires the interaction between the distal sub-apical mesenchyme and the apical ectodermal ridge (AER) that involve the separate implementation of coordinated and tissue-specific genetic programs.

Results: Here, we produce and analyze the transcriptomes of both distal limb mesenchymal progenitors and the overlying ectodermal cells, following time-coursed dissections that cover from limb bud initiation to fully patterned limbs. The comparison of transcriptomes within each layer as well as between layers over time, allowed the identification of specific transcriptional signatures for each of the developmental stages. Special attention was given to the identification of genes whose transcription dynamics suggest a previously unnoticed role in the context of limb development and also to signaling pathways enriched between layers.

Conclusion: We interpret the transcriptomic data in light of the known development pattern and we conclude that a major transcriptional transition occurs in distal limb buds between E9.5 and E10.5, coincident with the switch from an early phase continuation of the signature of trunk progenitors, related to the initial proximo distal specification, to a late intrinsic phase of development.
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http://dx.doi.org/10.1002/dvdy.394DOI Listing
July 2021

Dbx2 regulation in limbs suggests interTAD sharing of enhancers.

Dev Dyn 2021 Sep 1;250(9):1280-1299. Epub 2021 Mar 1.

Department of Genetics and Evolution, University of Geneva, Geneva, Switzerland.

Background: During tetrapod limb development, the HOXA13 and HOXD13 transcription factors are critical for the emergence and organization of the autopod, the most distal aspect where digits will develop. Since previous work had suggested that the Dbx2 gene is a target of these factors, we set up to analyze in detail this potential regulatory interaction.

Results: We show that HOX13 proteins bind to mammalian-specific sequences at the vicinity of the Dbx2 locus that have enhancer activity in developing digits. However, the functional inactivation of the DBX2 protein did not elicit any particular phenotype related to Hox genes inactivation in digits, suggesting either redundant or compensatory mechanisms. We report that the neighboring Nell2 and Ano6 genes are also expressed in distal limb buds and are in part controlled by the same Dbx2 enhancers despite being localized into two different topologically associating domains (TADs) flanking the Dbx2 locus.

Conclusions: We conclude that Hoxa13 and Hoxd genes cooperatively activate Dbx2 expression in developing digits through binding to mammalian specific regulatory sequences in the Dbx2 neighborhood. Furthermore, these enhancers can overcome TAD boundaries in either direction to co-regulate a set of genes located in distinct chromatin domains.
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http://dx.doi.org/10.1002/dvdy.303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451760PMC
September 2021

Chromatin topology and the timing of enhancer function at the locus.

Proc Natl Acad Sci U S A 2020 12 23;117(49):31231-31241. Epub 2020 Nov 23.

Department of Genetics and Evolution, University of Geneva, 1211 Geneva, Switzerland;

The gene cluster is critical for proper limb formation in tetrapods. In the emerging limb buds, different subgroups of genes respond first to a proximal regulatory signal, then to a distal signal that organizes digits. These two regulations are exclusive from one another and emanate from two distinct topologically associating domains (TADs) flanking , both containing a range of appropriate enhancer sequences. The telomeric TAD (T-DOM) contains several enhancers active in presumptive forearm cells and is divided into two sub-TADs separated by a CTCF-rich boundary, which defines two regulatory submodules. To understand the importance of this particular regulatory topology to control gene transcription in time and space, we either deleted or inverted this sub-TAD boundary, eliminated the CTCF binding sites, or inverted the entire T-DOM to exchange the respective positions of the two sub-TADs. The effects of such perturbations on the transcriptional regulation of genes illustrate the requirement of this regulatory topology for the precise timing of gene activation. However, the spatial distribution of transcripts was eventually resumed, showing that the presence of enhancer sequences, rather than either their exact topology or a particular chromatin architecture, is the key factor. We also show that the affinity of enhancers to find their natural target genes can overcome the presence of both a strong TAD border and an unfavorable orientation of CTCF sites.
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http://dx.doi.org/10.1073/pnas.2015083117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733857PMC
December 2020

Mammalian-specific ectodermal enhancers control the expression of genes in developing nails and hair follicles.

Proc Natl Acad Sci U S A 2020 12 16;117(48):30509-30519. Epub 2020 Nov 16.

Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas-Universidad de Cantabria-Sociedad para el Desarrollo de Cantabria, 39011 Santander, Spain;

Vertebrate genes are critical for the establishment of structures during the development of the main body axis. Subsequently, they play important roles either in organizing secondary axial structures such as the appendages, or during homeostasis in postnatal stages and adulthood. Here, we set up to analyze their elusive function in the ectodermal compartment, using the mouse limb bud as a model. We report that the gene cluster was co-opted to be transcribed in the distal limb ectoderm, where it is activated following the rule of temporal colinearity. These ectodermal cells subsequently produce various keratinized organs such as nails or claws. Accordingly, deletion of the cluster led to mice lacking nails (anonychia), a condition stronger than the previously reported loss of function of , which is the causative gene of the ectodermal dysplasia 9 (ECTD9) in human patients. We further identified two mammalian-specific ectodermal enhancers located upstream of the gene cluster, which together regulate gene expression in the hair and nail ectodermal organs. Deletion of these regulatory elements alone or in combination revealed a strong quantitative component in the regulation of genes in the ectoderm, suggesting that these two enhancers may have evolved along with the mammalian taxon to provide the level of HOXC proteins necessary for the full development of hair and nail.
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http://dx.doi.org/10.1073/pnas.2011078117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720164PMC
December 2020

pyGenomeTracks: reproducible plots for multivariate genomic datasets.

Bioinformatics 2021 04;37(3):422-423

Bioinformatics Group, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.

Motivation: Generating publication ready plots to display multiple genomic tracks can pose a serious challenge. Making desirable and accurate figures requires considerable effort. This is usually done by hand or using a vector graphic software.

Results: pyGenomeTracks (PGT) is a modular plotting tool that easily combines multiple tracks. It enables a reproducible and standardized generation of highly customizable and publication ready images.

Availability And Implementation: PGT is available through a graphical interface on https://usegalaxy.eu and through the command line. It is provided on conda via the bioconda channel, on pip and it is openly developed on github: https://github.com/deeptools/pyGenomeTracks.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058774PMC
April 2021

A complex regulatory landscape involved in the development of mammalian external genitals.

Elife 2020 04 17;9. Epub 2020 Apr 17.

School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

Developmental genes are often controlled by large regulatory landscapes matching topologically associating domains (TADs). In various contexts, the associated chromatin backbone is modified by specific enhancer-enhancer and enhancer-promoter interactions. We used a TAD flanking the mouse cluster to study how these regulatory architectures are formed and deconstructed once their function achieved. We describe this TAD as a functional unit, with several regulatory sequences acting together to elicit a transcriptional response. With one exception, deletion of these sequences didn't modify the transcriptional outcome, a result at odds with a conventional view of enhancer function. The deletion and inversion of a CTCF site located near these regulatory sequences did not affect transcription of the target gene. Slight modifications were nevertheless observed, in agreement with the loop extrusion model. We discuss these unexpected results considering both conventional and alternative explanations relying on the accumulation of poorly specific factors within the TAD backbone.
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http://dx.doi.org/10.7554/eLife.52962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185996PMC
April 2020

Impact of genome architecture on the functional activation and repression of Hox regulatory landscapes.

BMC Biol 2019 07 12;17(1):55. Epub 2019 Jul 12.

Laboratory of Developmental Genomics, Department of Genetics and Evolution, University of Geneva, 1211, Geneva 4, Switzerland.

Background: The spatial organization of the mammalian genome relies upon the formation of chromatin domains of various scales. At the level of gene regulation in cis, collections of enhancer sequences define large regulatory landscapes that usually match with the presence of topologically associating domains (TADs). These domains often contain ranges of enhancers displaying similar or related tissue specificity, suggesting that in some cases, such domains may act as coherent regulatory units, with a global on or off state. By using the HoxD gene cluster, which specifies the topology of the developing limbs via highly orchestrated regulation of gene expression, as a paradigm, we investigated how the arrangement of regulatory domains determines their activity and function.

Results: Proximal and distal cells in the developing limb express different levels of Hoxd genes, regulated by flanking 3' and 5' TADs, respectively. We characterized the effect of large genomic rearrangements affecting these two TADs, including their fusion into a single chromatin domain. We show that, within a single hybrid TAD, the activation of both proximal and distal limb enhancers globally occurred as when both TADs are intact. However, the activity of the 3' TAD in distal cells is generally increased in the fused TAD, when compared to wild type where it is silenced. Also, target gene activity in distal cells depends on whether or not these genes had previously responded to proximal enhancers, which determines the presence or absence of H3K27me3 marks. We also show that the polycomb repressive complex 2 is mainly recruited at the Hox gene cluster and can extend its coverage to far-cis regulatory sequences as long as confined to the neighboring TAD structure.

Conclusions: We conclude that antagonistic limb proximal and distal enhancers can exert their specific effects when positioned into the same TAD and in the absence of their genuine target genes. We also conclude that removing these target genes reduced the coverage of a regulatory landscape by chromatin marks associated with silencing, which correlates with its prolonged activity in time.
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http://dx.doi.org/10.1186/s12915-019-0677-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626364PMC
July 2019

The constrained architecture of mammalian gene clusters.

Proc Natl Acad Sci U S A 2019 07 17;116(27):13424-13433. Epub 2019 Jun 17.

School of Life Sciences, Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland;

In many animal species with a bilateral symmetry, genes are clustered either at one or at several genomic loci. This organization has a functional relevance, as the transcriptional control applied to each gene depends upon its relative position within the gene cluster. It was previously noted that vertebrate clusters display a much higher level of genomic organization than their invertebrate counterparts. The former are always more compact than the latter, they are generally devoid of repeats and of interspersed genes, and all genes are transcribed by the same DNA strand, suggesting that particular factors constrained these clusters toward a tighter structure during the evolution of the vertebrate lineage. Here, we investigate the importance of uniform transcriptional orientation by engineering several alleles within the cluster, such as to invert one or several transcription units, with or without a neighboring CTCF site. We observe that the association between the tight structure of mammalian clusters and their regulation makes inversions likely detrimental to the proper implementation of this complex genetic system. We propose that the consolidation of clusters in vertebrates, including transcriptional polarity, evolved in conjunction with the emergence of global gene regulation via the flanking regulatory landscapes, to optimize a coordinated response of selected subsets of target genes in .
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http://dx.doi.org/10.1073/pnas.1904602116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613147PMC
July 2019

Similarities and differences in the regulation of HoxD genes during chick and mouse limb development.

PLoS Biol 2018 11 26;16(11):e3000004. Epub 2018 Nov 26.

School of Life Sciences, Federal Institute of Technology, Lausanne, Lausanne, Switzerland.

In all tetrapods examined thus far, the development and patterning of limbs require the activation of gene members of the HoxD cluster. In mammals, they are regulated by a complex bimodal process that controls first the proximal patterning and then the distal structure. During the shift from the former to the latter regulation, this bimodal regulatory mechanism allows the production of a domain with low Hoxd gene expression, at which both telomeric (T-DOM) and centromeric regulatory domains (C-DOM) are silent. These cells generate the future wrist and ankle articulations. We analyzed the implementation of this regulatory mechanism in chicken, i.e., in an animal for which large morphological differences exist between fore- and hindlimbs. We report that although this bimodal regulation is globally conserved between the mouse and the chick, some important modifications evolved at least between these two model systems, in particular regarding the activity of specific enhancers, the width of the TAD boundary separating the two regulations, and the comparison between the forelimb versus hindlimb regulatory controls. At least one aspect of these regulations seems to be more conserved between chick and bats than with mouse, which may relate to the extent to which forelimbs and hindlimbs of these various animals differ in their morphologies.
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http://dx.doi.org/10.1371/journal.pbio.3000004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283595PMC
November 2018

The ALK receptor in sympathetic neuron development and neuroblastoma.

Cell Tissue Res 2018 05 27;372(2):325-337. Epub 2018 Jan 27.

Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe University Frankfurt, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany.

The ALK gene encodes a tyrosine kinase receptor characterized by an expression pattern mainly restricted to the developing central and peripheral nervous systems. In 2008, the discovery of ALK activating mutations in neuroblastoma, a tumor of the sympathetic nervous system, represented a breakthrough in the understanding of the pathogenesis of this pediatric cancer and established mutated ALK as a tractable therapeutic target for precision medicine. Subsequent studies addressed the identity of ALK ligands, as well as its physiological function in the sympathoadrenal lineage, its role in neuroblastoma development and the signaling pathways triggered by mutated ALK. This review focuses on these different aspects of the ALK biology and summarizes the various therapeutic strategies relying on ALK inhibition in neuroblastoma, either as monotherapies or combinatory treatments.
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http://dx.doi.org/10.1007/s00441-017-2784-8DOI Listing
May 2018

Activated ALK signals through the ERK-ETV5-RET pathway to drive neuroblastoma oncogenesis.

Oncogene 2018 03 11;37(11):1417-1429. Epub 2018 Jan 11.

Institut Curie, PSL Research University, Inserm U830, Equipe Labellisée Ligue contre le Cancer, Paris, France.

Activating mutations of the ALK receptor occur in a subset of neuroblastoma tumors. We previously demonstrated that Alk mutations cooperate with MYCN overexpression to induce neuroblastoma in mice and identified Ret as being strongly upregulated in MYCN/Alk tumors. By a genetic approach in vivo, we now document an oncogenic cooperation between activated Ret and MYCN overexpression in neuroblastoma formation. We show that MYCN/Ret tumors exhibit histological features and expression profiles close to MYCN/Alk tumors. We show that RET transcript levels decrease precedes RET protein levels decrease upon ALK inhibition in neuroblastoma cell lines. Etv5 was identified as a candidate transcription factor regulating Ret expression from murine MYCN/Alk tumor transcriptomic data. We demonstrate that ETV5 is regulated both at the protein and mRNA levels upon ALK activation or inhibition in neuroblastoma cell lines and that this regulation precedes RET modulation. We document that ALK activation induces ETV5 protein upregulation through stabilization in a MEK/ERK-dependent manner. We show that RNAi-mediated inhibition of ETV5 decreases RET expression. Reporter assays indicate that ETV5 is able to drive RET gene transcription. ChIP-seq analysis confirmed ETV5 binding on the RET promoter and identified an enhancer upstream of the promoter. Finally, we demonstrate that combining RET and ALK inhibitors reduces tumor growth more efficiently than each single agent in MYCN and Alk-driven murine neuroblastoma. Altogether, these results define the ERK-ETV5-RET pathway as a critical axis driving neuroblastoma oncogenesis downstream of activated ALK.
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http://dx.doi.org/10.1038/s41388-017-0039-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168456PMC
March 2018

The cluster is a dynamic and resilient TAD boundary controlling the segregation of antagonistic regulatory landscapes.

Genes Dev 2017 11 22;31(22):2264-2281. Epub 2017 Dec 22.

Department of Genetics and Evolution, University of Geneva, 1205 Geneva, Switzerland.

The mammalian cluster lies between two topologically associating domains (TADs) matching distinct enhancer-rich regulatory landscapes. During limb development, the telomeric TAD controls the early transcription of genes in forearm cells, whereas the centromeric TAD subsequently regulates more posterior genes in digit cells. Therefore, the TAD boundary prevents the terminal gene from responding to forearm enhancers, thereby allowing proper limb patterning. To assess the nature and function of this CTCF-rich DNA region in embryos we compared chromatin interaction profiles between proximal and distal limb bud cells isolated from mutant stocks where various parts of this boundary region were removed. The resulting progressive release in boundary effect triggered inter-TAD contacts, favored by the activity of the newly accessed enhancers. However, the boundary was highly resilient, and only a 400-kb deletion, including the whole-gene cluster, was eventually able to merge the neighboring TADs into a single structure. In this unified TAD, both proximal and distal limb enhancers nevertheless continued to work independently over a targeted transgenic reporter construct. We propose that the whole cluster is a dynamic TAD border and that the exact boundary position varies depending on both the transcriptional status and the developmental context.
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http://dx.doi.org/10.1101/gad.307769.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769770PMC
November 2017

Large scale genomic reorganization of topological domains at the HoxD locus.

Genome Biol 2017 08 7;18(1):149. Epub 2017 Aug 7.

School of Life Sciences, Ecole Polytechnique Fédérale, 1015, Lausanne, Switzerland.

Background: The transcriptional activation of HoxD genes during mammalian limb development involves dynamic interactions with two topologically associating domains (TADs) flanking the HoxD cluster. In particular, the activation of the most posterior HoxD genes in developing digits is controlled by regulatory elements located in the centromeric TAD (C-DOM) through long-range contacts.

Results: To assess the structure-function relationships underlying such interactions, we measured compaction levels and TAD discreteness using a combination of chromosome conformation capture (4C-seq) and DNA FISH. We assessed the robustness of the TAD architecture by using a series of genomic deletions and inversions that impact the integrity of this chromatin domain and that remodel long-range contacts. We report multi-partite associations between HoxD genes and up to three enhancers. We find that the loss of native chromatin topology leads to the remodeling of TAD structure following distinct parameters.

Conclusions: Our results reveal that the recomposition of TAD architectures after large genomic re-arrangements is dependent on a boundary-selection mechanism in which CTCF mediates the gating of long-range contacts in combination with genomic distance and sequence specificity. Accordingly, the building of a recomposed TAD at this locus depends on distinct functional and constitutive parameters.
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http://dx.doi.org/10.1186/s13059-017-1278-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547506PMC
August 2017

Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma.

Oncotarget 2014 May;5(9):2688-702

Inserm U830, 26 rue d'Ulm, 75005 Paris, France.

Activating mutations of the ALK (Anaplastic lymphoma Kinase) gene have been identified in sporadic and familial cases of neuroblastoma, a cancer of early childhood arising from the sympathetic nervous system (SNS). To decipher ALK function in neuroblastoma predisposition and oncogenesis, we have characterized knock-in (KI) mice bearing the two most frequent mutations observed in neuroblastoma patients. A dramatic enlargement of sympathetic ganglia is observed in AlkF1178L mice from embryonic to adult stages associated with an increased proliferation of sympathetic neuroblasts from E14.5 to birth. In a MYCN transgenic context, the F1178L mutation displays a higher oncogenic potential than the R1279Q mutation as evident from a shorter latency of tumor onset. We show that tumors expressing the R1279Q mutation are sensitive to ALK inhibition upon crizotinib treatment. Furthermore, our data provide evidence that activated ALK triggers RET upregulation in mouse sympathetic ganglia at birth as well as in murine and human neuroblastoma. Using vandetanib, we show that RET inhibition strongly impairs tumor growth in vivo in both MYCN/KI AlkR1279Q and MYCN/KI AlkF1178L mice. Altogether, our findings demonstrate the critical role of activated ALK in SNS development and pathogenesis and identify RET as a therapeutic target in ALK mutated neuroblastoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058037PMC
http://dx.doi.org/10.18632/oncotarget.1883DOI Listing
May 2014

Hyperactivation of Alk induces neonatal lethality in knock-in AlkF1178L mice.

Oncotarget 2014 May;5(9):2703-13

Inserm U830, Paris, France;

The ALK (Anaplastic Lymphoma Kinase) gene encodes a tyrosine kinase receptor preferentially expressed in the central and peripheral nervous systems. A syndromic presentation associating congenital neuroblastoma with severe encephalopathy and an abnormal shape of the brainstem has been described in patients harbouring de novo germline F1174V and F1245V ALK mutations. Here, we investigated the phenotype of knock-in (KI) mice bearing the AlkF1178L mutation (F1174L in human). Although heterozygous KI mice did not reproduce the severe breathing and feeding difficulties observed in human patients, behavioral tests documented a reduced activity during dark phases and an increased anxiety of mutated mice. Matings of heterozygotes yielded the expected proportions of wild-type, heterozygotes and homozygotes at birth but a high neonatal lethality was noticed for homozygotes. We documented Alk expression in several motor nuclei of the brainstem involved in the control of sucking and swallowing. Evaluation of basic physiological functions 12 hours after birth revealed slightly more apneas but a dramatic reduced milk intake for homozygotes compared to control littermates. Overall, our data demonstrate that Alk activation above a critical threshold is not compatible with survival in mice, in agreement with the extremely severe phenotype of patients carrying aggressive de novo ALK germline mutations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058038PMC
http://dx.doi.org/10.18632/oncotarget.1882DOI Listing
May 2014
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