Publications by authors named "Fabrice Chatonnet"

24 Publications

  • Page 1 of 1

Plasmablasts derive from CD23- activated B cells after the extinction of IL-4/STAT6 signaling and IRF4 induction.

Blood 2021 Mar;137(9):1166-1180

Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, Unité Mixte de Recherche (UMR) S1236, Rennes, France; and.

The terminal differentiation of B cells into antibody-secreting cells (ASCs) is a critical component of adaptive immune responses. However, it is a very sensitive process, and dysfunctions lead to a variety of lymphoproliferative neoplasias including germinal center-derived lymphomas. To better characterize the late genomic events that drive the ASC differentiation of human primary naive B cells, we used our in vitro differentiation system and a combination of RNA sequencing and Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC sequencing). We discovered 2 mechanisms that drive human terminal B-cell differentiation. First, after an initial response to interleukin-4 (IL-4), cells that were committed to an ASC fate downregulated the CD23 marker and IL-4 signaling, whereas cells that maintained IL-4 signaling did not differentiate. Second, human CD23- cells also increased IRF4 protein to levels required for ASC differentiation, but they did that independently of the ubiquitin-mediated degradation process previously described in mice. Finally, we showed that CD23- cells carried the imprint of their previous activated B-cell status, were precursors of plasmablasts, and had a phenotype similar to that of in vivo preplasmablasts. Altogether, our results provide an unprecedented genomic characterization of the fate decision between activated B cells and plasmablasts, which provides new insights into the pathological mechanisms that drive lymphoma biology.
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http://dx.doi.org/10.1182/blood.2020005083DOI Listing
March 2021

Integrative Analysis of Cell Crosstalk within Follicular Lymphoma Cell Niche: Towards a Definition of the FL Supportive Synapse.

Cancers (Basel) 2020 Oct 5;12(10). Epub 2020 Oct 5.

UMR_S 1236, Univ Rennes, INSERM, Établissement Français du Sang (EFS) Bretagne, LabEx IGO, F-35000 Rennes, France.

Follicular lymphoma (FL), the most frequent indolent non-Hodgkin's B cell lymphoma, is considered as a prototypical centrocyte-derived lymphoma, dependent on a specific microenvironment mimicking the normal germinal center (GC). In agreement, several FL genetic alterations affect the crosstalk between malignant B cells and surrounding cells, including stromal cells and follicular helper T cells (Tfh). In our study, we sought to deconvolute this complex FL supportive synapse by comparing the transcriptomic profiles of GC B cells, Tfh, and stromal cells, isolated from normal versus FL tissues, in order to identify tumor-specific pathways. In particular, we highlighted a high expression of and in FL B cells that could favor the activation of FL Tfh overexpressing IFNG, able in turn to stimulate FL B cells without triggering MHC (major histocompatibility) class II expression. Moreover, the glycoprotein clusterin was found up-regulated in FL stromal cells and could promote FL B cell adhesion. Finally, besides its expression on Tfh, CD200 was found overexpressed on tumor B cells and could contribute to the induction of the immunosuppressive enzyme indoleamine-2,3 dioxygenase by CD200R-expressing dendritic cells. Altogether our findings led us to outline the contribution of major signals provided by the FL microenvironment and their interactions with malignant FL B cells.
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http://dx.doi.org/10.3390/cancers12102865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599549PMC
October 2020

The hydroxymethylome of multiple myeloma identifies FAM72D as a 1q21 marker linked to proliferation.

Haematologica 2020 03 20;105(3):774-783. Epub 2019 Jun 20.

SPARTE, IGDR, CNRS UMR6290, University Rennes 1, Rennes, France

Cell identity relies on the cross-talk between genetics and epigenetics and their impact on gene expression. Oxidation of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) is the first step of an active DNA demethylation process occurring mainly at enhancers and gene bodies and, as such, participates in processes governing cell identity in normal and pathological conditions. Although genetic alterations are well documented in multiple myeloma (MM), epigenetic alterations associated with this disease have not yet been thoroughly analyzed. To gain insight into the biology of MM, genome-wide 5hmC profiles were obtained and showed that regions enriched in this modified base overlap with MM enhancers and super enhancers and are close to highly expressed genes. Through the definition of a MM-specific 5hmC signature, we identified FAM72D as a poor prognostic gene located on 1q21, a region amplified in high risk myeloma. We further uncovered that FAM72D functions as part of the FOXM1 transcription factor network controlling cell proliferation and survival and we evidenced an increased sensitivity of cells expressing high levels of FOXM1 and FAM72 to epigenetic drugs targeting histone deacetylases and DNA methyltransferases.
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http://dx.doi.org/10.3324/haematol.2019.222133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049362PMC
March 2020

The hydroxymethylome of multiple myeloma identifies FAM72D as a 1q21 marker linked to proliferation.

Haematologica 2020 03 20;105(3):774-783. Epub 2019 Jun 20.

SPARTE, IGDR, CNRS UMR6290, University Rennes 1, Rennes, France

Cell identity relies on the cross-talk between genetics and epigenetics and their impact on gene expression. Oxidation of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) is the first step of an active DNA demethylation process occurring mainly at enhancers and gene bodies and, as such, participates in processes governing cell identity in normal and pathological conditions. Although genetic alterations are well documented in multiple myeloma (MM), epigenetic alterations associated with this disease have not yet been thoroughly analyzed. To gain insight into the biology of MM, genome-wide 5hmC profiles were obtained and showed that regions enriched in this modified base overlap with MM enhancers and super enhancers and are close to highly expressed genes. Through the definition of a MM-specific 5hmC signature, we identified FAM72D as a poor prognostic gene located on 1q21, a region amplified in high risk myeloma. We further uncovered that FAM72D functions as part of the FOXM1 transcription factor network controlling cell proliferation and survival and we evidenced an increased sensitivity of cells expressing high levels of FOXM1 and FAM72 to epigenetic drugs targeting histone deacetylases and DNA methyltransferases.
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http://dx.doi.org/10.3324/haematol.2019.222133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049362PMC
March 2020

Cell-Cycle-Dependent Reconfiguration of the DNA Methylome during Terminal Differentiation of Human B Cells into Plasma Cells.

Cell Rep 2015 Nov 22;13(5):1059-71. Epub 2015 Oct 22.

INSERM, UMR917, Equipe labellisée Ligue contre le Cancer, Rennes 35043, France; Pôle de Biologie, Centre Hospitalier Universitaire (CHU), Rennes 35033, France; Université de Rennes 1, Rennes 35065, France; Etablissement Français du Sang de Bretagne, Rennes 35016, France. Electronic address:

Molecular mechanisms underlying terminal differentiation of B cells into plasma cells are major determinants of adaptive immunity but remain only partially understood. Here we present the transcriptional and epigenomic landscapes of cell subsets arising from activation of human naive B cells and differentiation into plasmablasts. Cell proliferation of activated B cells was linked to a slight decrease in DNA methylation levels, but followed by a committal step in which an S phase-synchronized differentiation switch was associated with an extensive DNA demethylation and local acquisition of 5-hydroxymethylcytosine at enhancers and genes related to plasma cell identity. Downregulation of both TGF-?1/SMAD3 signaling and p53 pathway supported this final step, allowing the emergence of a CD23-negative subpopulation in transition from B cells to plasma cells. Remarkably, hydroxymethylation of PRDM1, a gene essential for plasma cell fate, was coupled to progression in S phase, revealing an intricate connection among cell cycle, DNA (hydroxy)methylation, and cell fate determination.
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http://dx.doi.org/10.1016/j.celrep.2015.09.051DOI Listing
November 2015

Direct and indirect consequences on gene expression of a thyroid hormone receptor alpha 1 mutation restricted to Sertoli cells.

Mol Reprod Dev 2014 Dec 8;81(12):1159-66. Epub 2014 Dec 8.

Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, INRA, CNRS, Cedex, France.

Thyroid hormone is required for the timely transition of Sertoli cells from proliferative to differentiating and maturing. This transition takes place during a critical developmental period in mammals, which in mice is the first post-natal week. In order to identify the underlying molecular mechanisms of this differentiation process, we used Cre/loxP technology to selectively block the function of the thyroid hormone receptor TRα1 in Sertoli cells. We then used RNA-seq to analyze the changes in gene expression induced in the post-natal testis. This differential analysis provides genetic clues to the initial testicular defects resulting from disrupted thyroid hormone signaling, and suggests that Sertoli cells influence germ cells soon after their birth.
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http://dx.doi.org/10.1002/mrd.22437DOI Listing
December 2014

Toxicogenomic analysis of the ability of brominated flame retardants TBBPA and BDE-209 to disrupt thyroid hormone signaling in neural cells.

Toxicology 2014 Nov 27;325:125-32. Epub 2014 Aug 27.

Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, INRA, Ecole Normale Supérieure de Lyon, 32-34 Avenue Tony Garnier, 69007 Lyon Cedex 07, France. Electronic address:

Brominated flame retardants are suspected to act as disruptors of thyroid hormone signaling. This raises the concern that they might affect children's cognitive functions by influencing thyroid hormone signaling in the developing brain. We present here an in vitro analysis of the ability of the most common compounds, tetrabromobisphenol A (TBBPA) and BDE-209, to alter thyroid hormone response based on a model neural cell line and genome-wide analysis of gene expression.
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http://dx.doi.org/10.1016/j.tox.2014.08.007DOI Listing
November 2014

Deciphering direct and indirect influence of thyroid hormone with mouse genetics.

Mol Endocrinol 2014 Apr 10;28(4):429-41. Epub 2014 Mar 10.

Université de Lyon, Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, Université Claude Bernard Lyon 1, École Normale, Supérieure de Lyon, Institut de Génomique Fonctionnelle de Lyon, Lyon, France.

T3, the active form of thyroid hormone, binds nuclear receptors that regulate the transcription of a large number of genes in many cell types. Unraveling the direct and indirect effect of this hormonal stimulation, and establishing links between these molecular events and the developmental and physiological functions of the hormone, is a major challenge. New mouse genetics tools, notably those based on Cre/loxP technology, are suitable to perform a multiscale analysis of T3 signaling and achieve this task.
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http://dx.doi.org/10.1210/me.2013-1414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414923PMC
April 2014

Purkinje cells and Bergmann glia are primary targets of the TRα1 thyroid hormone receptor during mouse cerebellum postnatal development.

Development 2014 Jan;141(1):166-75

Université de Lyon, CNRS, INRA, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, Institut de Génomique Fonctionnelle de Lyon, F-69364 Lyon, Cedex 07, France.

Thyroid hormone is necessary for normal development of the central nervous system, as shown by the severe mental retardation syndrome affecting hypothyroid patients with low levels of active thyroid hormone. The postnatal defects observed in hypothyroid mouse cerebellum are recapitulated in mice heterozygous for a dominant-negative mutation of Thra, the gene encoding the ubiquitous TRα1 receptor. Using CRE/loxP-mediated conditional expression approach, we found that this mutation primarily alters the differentiation of Purkinje cells and Bergmann glia, two cerebellum-specific cell types. These primary defects indirectly affect cerebellum development in a global manner. Notably, the inward migration and terminal differentiation of granule cell precursors is impaired. Therefore, despite the broad distribution of its receptors, thyroid hormone targets few cell types that exert a predominant role in the network of cellular interactions that govern normal cerebellum maturation.
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http://dx.doi.org/10.1242/dev.103226DOI Listing
January 2014

Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells.

Proc Natl Acad Sci U S A 2013 Feb 4;110(8):E766-75. Epub 2013 Feb 4.

Université de Lyon, Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique, École Normale Supérieure de Lyon, 69364 Lyon Cedex 07, France.

TRα1 and TRβ1, the two main thyroid hormone receptors in mammals, are transcription factors that share similar properties. However, their respective functions are very different. This functional divergence might be explained in two ways: it can reflect different expression patterns or result from different intrinsic properties of the receptors. We tested this second hypothesis by comparing the repertoires of 3,3',5-triiodo-L-thyronine (T3)-responsive genes of two neural cell lines, expressing either TRα1 or TRβ1. Using transcriptome analysis, we found that a substantial fraction of the T3 target genes display a marked preference for one of the two receptors. So when placed alone in identical situations, the two receptors have different repertoires of target genes. Chromatin occupancy analysis, performed at a genome-wide scale, revealed that TRα1 and TRβ1 cistromes were also different. However, receptor-selective regulation of T3 target genes did not result from receptor-selective chromatin occupancy of their promoter regions. We conclude that modification of TRα1 and TRβ1 intrinsic properties contributes in a large part to the divergent evolution of the receptors' function, at least during neurodevelopment.
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http://dx.doi.org/10.1073/pnas.1210626110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581916PMC
February 2013

Thyroid hormone triggers the developmental loss of axonal regenerative capacity via thyroid hormone receptor α1 and krüppel-like factor 9 in Purkinje cells.

Proc Natl Acad Sci U S A 2012 Aug 13;109(35):14206-11. Epub 2012 Aug 13.

Université Pierre et Marie Curie (UPMC) Paris 06, Unité Mixte de Recherche 7102, 75005 Paris, France.

Neurons in the CNS of higher vertebrates lose their ability to regenerate their axons at a stage of development that coincides with peak circulating thyroid hormone (T(3)) levels. Here, we examined whether this peak in T(3) is involved in the loss of axonal regenerative capacity in Purkinje cells (PCs). This event occurs at the end of the first postnatal week in mice. Using organotypic culture, we found that the loss of axon regenerative capacity was triggered prematurely by early exposure of mouse PCs to T(3), whereas it was delayed in the absence of T(3). Analysis of mutant mice showed that this effect was mainly mediated by the T(3) receptor α1. Using gain- and loss-of-function approaches, we also showed that Krüppel-like factor 9 was a key mediator of this effect of T(3). These results indicate that the sudden physiological increase in T(3) during development is involved in the onset of the loss of axon regenerative capacity in PCs. This loss of regenerative capacity might be part of the general program triggered by T(3) throughout the body, which adapts the animal to its postnatal environment.
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http://dx.doi.org/10.1073/pnas.1119853109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435228PMC
August 2012

Genome-wide search reveals the existence of a limited number of thyroid hormone receptor alpha target genes in cerebellar neurons.

PLoS One 2012 7;7(5):e30703. Epub 2012 May 7.

Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, INRA, École Normale Supérieure de Lyon, Lyon, France.

Thyroid hormone (T3) has a major influence on cerebellum post-natal development. The major phenotypic landmark of exposure to low levels of T3 during development (hypothyroidism) in the cerebellum is the retarded inward migration of the most numerous cell type, granular neurons. In order to identify the direct genetic regulation exerted by T3 on cerebellar neurons and their precursors, we used microarray RNA hybridization to perform a time course analysis of T3 induced gene expression in primary cultures of cerebellar neuronal cell. These experiments suggest that we identified a small set of genes which are directly regulated, both in vivo and in vitro, during cerebellum post-natal development. These modest changes suggest that T3 does not acts directly on granular neurons and mainly indirectly influences the cellular interactions taking place during development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030703PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3346809PMC
September 2012

A bimodal influence of thyroid hormone on cerebellum oligodendrocyte differentiation.

Mol Endocrinol 2012 Apr 23;26(4):608-18. Epub 2012 Feb 23.

Université Lyon 1, Centre National de la Recherche Scientifique, Institut de la Recherché Agronomique, Ecole Normale Supérieure de Lyon, 69364 Lyon Cedex 07, France.

Thyroid hormone (T(3)) can trigger a massive differentiation of cultured oligodendrocytes precursor cells (OPC) by binding the nuclear T(3) receptor α1 (TRα1). Whether this reflects a physiological function of TRα1 remains uncertain. Using a recently generated mouse model, in which CRE/loxP recombination is used to block its function, we show that TRα1 acts at two levels for the in vivo differentiation of OPC in mouse cerebellum. At the early postnatal stage, it promotes the secretion of several neurotrophic factors by acting in Purkinje neurons and astrocytes, defining an environment suitable for OPC differentiation. At later stages, TRα1 acts in a cell-autonomous manner to ensure the complete arrest of OPC proliferation. These data explain contradictory observations made on various models and outline the importance of T(3) signaling both for synchronizing postnatal neurodevelopment and restraining OPC proliferation in adult brain.
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http://dx.doi.org/10.1210/me.2011-1316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417134PMC
April 2012

Thyroid hormone action in cerebellum and cerebral cortex development.

J Thyroid Res 2011 16;2011:145762. Epub 2011 Jun 16.

Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, Université de Lyon, UMR CNRS 5242, 46 allée d'Italie, 69364 Lyon Cedex 07, France.

Thyroid hormones (TH, including the prohormone thyroxine (T4) and its active deiodinated derivative 3,3',5-triiodo-L-thyronine (T3)) are important regulators of vertebrates neurodevelopment. Specific transporters and deiodinases are required to ensure T3 access to the developing brain. T3 activates a number of differentiation processes in neuronal and glial cell types by binding to nuclear receptors, acting directly on transcription. Only few T3 target genes are currently known. Deeper investigations are urgently needed, considering that some chemicals present in food are believed to interfere with T3 signaling with putative neurotoxic consequences.
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http://dx.doi.org/10.4061/2011/145762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134109PMC
November 2011

Severe impairment of cerebellum development in mice expressing a dominant-negative mutation inactivating thyroid hormone receptor alpha1 isoform.

Dev Biol 2011 Aug 20;356(2):350-8. Epub 2011 May 20.

Université de Lyon, CNRS, INRA, Université Claude Bernard Lyon 1, École Normale, Supérieure de Lyon, Institut de Génomique Fonctionnelle de Lyon, France

Thyroid hormone deficiency is known to deeply affect cerebellum post-natal development. We present here a detailed analysis of the phenotype of a recently generated mouse model, expressing a dominant-negative TRα1 mutation. Although hormonal level is not affected, the cerebellum of these mice displays profound alterations in neuronal and glial differentiation, which are reminiscent of congenital hypothyroidism, indicating a predominant function of this receptor isoform in normal cerebellum development. Some of the observed effects might result from the cell autonomous action of the mutation, while others are more likely to result from a reduction in neurotrophic factor production.
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http://dx.doi.org/10.1016/j.ydbio.2011.05.657DOI Listing
August 2011

Distinct roles of Hoxa2 and Krox20 in the development of rhythmic neural networks controlling inspiratory depth, respiratory frequency, and jaw opening.

Neural Dev 2007 Sep 26;2:19. Epub 2007 Sep 26.

NGI, UPR 2216, Institut de Neurobiologie Alfred Fessard IFR2218, Centre National de Recherche Scientifique, F-91198 Gif sur Yvette Cedex, France.

Background: Little is known about the involvement of molecular determinants of segmental patterning of rhombomeres (r) in the development of rhythmic neural networks in the mouse hindbrain. Here, we compare the phenotypes of mice carrying targeted inactivations of Hoxa2, the only Hox gene expressed up to r2, and of Krox20, expressed in r3 and r5. We investigated the impact of such mutations on the neural circuits controlling jaw opening and breathing in newborn mice, compatible with Hoxa2-dependent trigeminal defects and direct regulation of Hoxa2 by Krox20 in r3.

Results: We found that Hoxa2 mutants displayed an impaired oro-buccal reflex, similarly to Krox20 mutants. In contrast, while Krox20 is required for the development of the rhythm-promoting parafacial respiratory group (pFRG) modulating respiratory frequency, Hoxa2 inactivation did not affect neonatal breathing frequency. Instead, we found that Hoxa2-/- but not Krox20-/- mutation leads to the elimination of a transient control of the inspiratory amplitude normally occurring during the first hours following birth. Tracing of r2-specific progenies of Hoxa2 expressing cells indicated that the control of inspiratory activity resides in rostral pontine areas and required an intact r2-derived territory.

Conclusion: Thus, inspiratory shaping and respiratory frequency are under the control of distinct Hox-dependent segmental cues in the mammalian brain. Moreover, these data point to the importance of rhombomere-specific genetic control in the development of modular neural networks in the mammalian hindbrain.
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http://dx.doi.org/10.1186/1749-8104-2-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2098766PMC
September 2007

Exposure to retinoic acid at the onset of hindbrain segmentation induces episodic breathing in mice.

Eur J Neurosci 2007 Jun;25(12):3526-36

Neurobiologie Génétique et Intégrative, UPR 2216, CNRS, Gif-sur-Yvette, France.

Hyperpnoeic episodic breathing (HEB), a cyclic waxing and waning of breathing, has been widely reported in pre-term neonates, patients with Joubert syndrome and adults (Cheyne-Stokes respiration) with congestive heart failure and brainstem infarction. We now provide a developmental mouse model of neonatal HEB. We used retinoic acid (RA) (0.5-10 mg/kg of maternal weight) to alter embryonic development of the respiratory neuronal network at the onset of hindbrain segmentation (7.5 days post-coitum). HEB was observed in vivo after RA treatment during post-natal days 1-7 but not in control animals. HEB persisted after reduction of the chemoafferent input by hypocapnic hyperoxia (100% O(2)). A large increase and decrease of the rhythm resembling an HEB episode was induced in vitro by stimulating the parafacial respiratory oscillator in treated but not in control neonates. Post-natal localization of the superior cerebellar peduncle and adjacent dorsal tegmentum was found to be abnormal in the pons of RA-treated juvenile mice. Thus, early developmental specifications in the rostral hindbrain are required for the development of neurones that stabilize the function of the respiratory rhythm generator, thereby preventing HEB during post-natal maturation.
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http://dx.doi.org/10.1111/j.1460-9568.2007.05609.xDOI Listing
June 2007

Cloning and analysis of Nkx6.3 during CNS and gastrointestinal development.

Gene Expr Patterns 2006 Jan 2;6(2):162-70. Epub 2005 Dec 2.

Umeå Centre for Molecular Medicine, UCMM, Umeå University, S-901 87 Umeå, Sweden.

Members of the Nkx family of homeodomain proteins are involved in a variety of developmental processes such as cell fate determination in the CNS and in the pancreas. Here we describe the cloning and developmental expression pattern of Nkx6.3, a new member of the Nkx6 subfamily of homeodomain proteins. Nkx6.3 is expressed in the developing CNS and gastro-intestinal tract. In contrast to Nkx6.1 and Nkx6.2 that are broadly expressed in ventral positions of the developing CNS, Nkx6.3 shows a remarkably selective expression in a subpopulation of differentiating V2 neurons at caudal hindbrain levels. The expression of Nkx6.3 at this level depends on the activity of other Nkx6 proteins. In the gut, Nkx6.3 is expressed in duodenal and glandular stomach endoderm and at the end of gestation Nkx6.3 became restricted to the base of the gastric units in the glandular stomach. The expression of Nkx6.3 overlapped with the expression of Nkx6.2 both in the CNS and in the gut. Transient Nkx6.2 expression was also detected in the developing pancreas. However, analysis of Nkx6.2(-/-) mice did not display any obvious aberrations of pancreatic or stomach development.
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http://dx.doi.org/10.1016/j.modgep.2005.06.012DOI Listing
January 2006

Breathing without acetylcholinesterase.

Adv Exp Med Biol 2004 ;551:165-70

NGI-Institut de Neurobiologie A Fessard--CNRS, Gif sur Yvette, France.

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http://dx.doi.org/10.1007/0-387-27023-x_25DOI Listing
March 2005

From hindbrain segmentation to breathing after birth: developmental patterning in rhombomeres 3 and 4.

Mol Neurobiol 2003 Dec;28(3):277-94

UPR 2216 Neurobiologie Génétique et Intégrative, Institut de Neurobiologie Alfred Fessard, CNRS, 1 avenue de la Terrasse, 91198 Gif-sur-Yvette, France.

Respiration is a rhythmic motor behavior that appears in the fetus and acquires a vital importance at birth. It is generated within central pattern-generating neuronal networks of the hindbrain. This region of the brain is of particular interest since it is the most understood part with respect to the cellular and molecular mechanisms that underlie its development. Hox paralogs and Hox-regulating genes kreisler/mafB and Krox20 are required for the normal formation of rhombomeres in vertebrate embryos. From studies of rhombomeres r3 and r4, the authors review mechanisms whereby these developmental genes may govern the early embryonic development of para-facial neuronal networks and specify patterns of motor activities operating throughout life. A model whereby the regional identity of progenitor cells can be abnormally specified in r3 and r4 after a mutation of these genes is proposed. Novel neuronal circuits may develop from some of these misspecified progenitors while others are eliminated, eventually affecting respiration and survival after birth.
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http://dx.doi.org/10.1385/mn:28:3:277DOI Listing
December 2003

Respiratory survival mechanisms in acetylcholinesterase knockout mouse.

Eur J Neurosci 2003 Sep;18(6):1419-27

Neurobiologie Génétique et Intégrative UPR2216, Institut de Neurobiologie Alfred Fessard IFR2218, C.N.R.S., 91198 Gif-sur-Yvette Cedex, France.

Cholinergic neurotransmission ensures muscle contraction and plays a role in the regulation of respiratory pattern in the brainstem. Inactivation of acetylcholinesterase (AChE) by organophosphates produces respiratory failure but AChE knockout mice survive to adulthood. Respiratory adaptation mechanisms which ensure survival of these mice were examined in vivo by whole body plethysmography and in vitro in the neonatal isolated brainstem preparation. AChE-/- mice presented no AChE activity but unaffected butyrylcholinesterase (BChE) activity. In vivo, bambuterol (50-500 microg/kg s.c.) decreased BChE activity peripherally but not in brain tissue and induced apnea and death in adult and neonate AChE-/- mice without affecting littermate AChE+/+ and +/- animals. In vitro, bath-applied bambuterol (1-100 microm) and tetraisopropylpyrophosphoramide (10-100 microm) decreased BChE activity in the brainstem but did not perturb central respiratory activity recorded from spinal nerve rootlets. In vitro, the cholinergic agonists muscarine (50-100 microm) and nicotine (0.5-10 microm) induced tonic activity in respiratory motoneurons and increased the frequency of inspiratory bursts in AChE+/+ and +/- animals. These effects were greatly attenuated in AChE-/- animals. The results suggest that, in mice lacking AChE, (i) BChE becomes essential for survival peripherally but plays no critical role in central rhythm-generating structures and (ii) a major adaptive mechanism for respiratory survival is the down-regulated response of central respiratory-related neurons and motoneurons to muscarinic and nicotinic agonists.
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http://dx.doi.org/10.1046/j.1460-9568.2003.02867.xDOI Listing
September 2003

Developmental molecular switches regulating breathing patterns in CNS.

Respir Physiol Neurobiol 2003 May;135(2-3):121-32

UPR 2216 Neurobiologie Génétique et Intégrative, Institut de Neurobiologie Alfred Fessard, C.N.R.S., 1, av. de la Terrasse, 91198, Gif-sur-Yvette, France.

The present paper presents some of the molecular switches that may operate at early embryonic stages to make development of the brainstem respiratory rhythm generator a robust and irreversible process. We concentrate on the role of transient Hox-related gene expression patterns in register with the regionalisation of the rhombencephalic neural tube along the antero-posterior axis. Using different recording and isolation procedures in chick embryos, we show that the hindbrain is subdivided at E1 into developmental units (rhombomeres) intrinsically able to produce rhythm generating neuronal circuits active at E5. At E6, intrinsic cues also allow a progressive maturation of episodic rhythm generators that persists after isolation of the hindbrain in vitro and requires odd/even rhombomeric interactions at E1. From these results and from respiratory pathologies observed in transgenic mice, we are beginning to understand that, despite diversity of breathing patterns and adaptations, there are links between developmental control genes and adult respiration.
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http://dx.doi.org/10.1016/s1569-9048(03)00031-4DOI Listing
May 2003

Early development of respiratory rhythm generation in mouse and chick.

Respir Physiol Neurobiol 2002 Jul;131(1-2):5-13

U.P.R. 2216, Neurobiologie Génétique et Intégrative, IFR 2118 Institut de Neurobiologie Alfred Fessard, C.N.R.S., 1, av. de la Terrasse, 91198 Gif-sur-Yvette, France.

We are investigating neuronal circuits resulting from conservative developmental mechanisms orchestrating the segmentation of the vertebrates hindbrain into compartments called rhombomeres (r). Segmentation transcription factors Hoxa1, Krox20 and kreisler are expressed in the future rhombomeres r4-r5, r3 and r5, r5-r6, respectively. In mice, the in vivo and in vitro analysis of neuronal groups after inactivation of these three genes revealed distinct postnatal respiratory phenotypes associated with defects of central respiratory controls resulting from deletion, neoformation or reconfiguration of modular circuits. In chick and mice, we have found neuronal rhythm generators that conform to the rhombomeric anatomical pattern as early as at the end of the segmentation. By isolating chick hindbrain segments in vitro, we have also identified rhombomeric motifs allowing the formation or deletion of a specific (GABAergic) rhythm-promoting module. Therefore, primordial rhombomeric organization of the hindbrain seems to determine a modular organization of the rhythmogenic network, thereby influencing later function of brainstem respiratory control networks.
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http://dx.doi.org/10.1016/s1569-9048(02)00033-2DOI Listing
July 2002

Different respiratory control systems are affected in homozygous and heterozygous kreisler mutant mice.

Eur J Neurosci 2002 Feb;15(4):684-92

Neurobiologie Génétique et Intégrative, UPR2216, Centre National de la Recherche Scientifique, Institut de Neurobiologie Alfred Fessard UFR 2218, 91198 Gif-sur-Yvette Cedex, France.

During embryonic development, restricted expression of the regulatory genes Krox20 and kreisler are involved in segmentation and antero-posterior patterning of the hindbrain neural tube. The analysis of transgenic mice in which specific rhombomeres (r) are eliminated points to an important role of segmentation in the generation of neuronal networks controlling vital rhythmic behaviours such as respiration. Thus, elimination of r3 and r5 in Krox20-/- mice suppresses a pontine antiapneic system (Jacquin et al., 1996). We now compare Krox20-/- to kreisler heterozygous (+/kr) and homozygous (kr/kr) mutant neonates. In +/kr mutant mice, we describe hyperactivity of the antiapneic system: analysis of rhythm generation in vitro revealed a pontine modification in keeping with abnormal cell specifications previously reported in r3 (Manzanares et al., 1999b). In kr/kr mice, elimination of r5 abolished all +/kr respiratory traits, suggesting that +/kr hyperactivity of the antiapneic system is mediated through r5-derived territories. Furthermore, collateral chemosensory pathways that normally mediate delayed responses to hypoxia and hyperoxia were not functional in kr/kr mice. We conclude that the pontine antiapneic system originates from r3r4, but not r5. A different rhythm-promoting system originates in r5 and kreisler controls the development of antiapneic and chemosensory signal transmission at this level.
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http://dx.doi.org/10.1046/j.1460-9568.2002.01909.xDOI Listing
February 2002