Patrick Collombat

Publications (34) View all

• Source

  Available from: Nouha Ben Othman

  Article: In vivo conversion of adult α-cells into β-like cells: a new research avenue in the context of type 1 diabetes.

  M Courtney, A Pfeifer, K Al-Hasani, E Gjernes, A Vieira, N Ben-Othman, P Collombat
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  ABSTRACT: Type 1 diabetes is caused by the loss of insulin-producing β-cells as a result of an autoimmune condition. Despite current therapeutic approaches aimed at restoring the insulin supply, complications caused by variations in glycaemia may still arise with age. There is therefore mounting interest in the establishment of alternative therapies. Most current approaches consist in designing rational protocols for in vitro or in vivo cell differentiation/reprogramming from a number of cell sources, including stem, progenitor or differentiated cells. Towards this ultimate goal, it is clear that we need to gain further insight into the interplay between signalling events and transcriptional networks that act in concert throughout pancreatic morphogenesis. This short review will therefore focus on the main events underlying pancreatic development with particular emphasis on the genetic determinants implicated, as well as on the relatively new concept of endocrine cell reprogramming, that is the conversion of pancreatic α-cells into cells displaying a β-cell phenotype.
  Diabetes Obesity and Metabolism 10/2011; 13 Suppl 1:47-52. · 3.38 Impact Factor
• Article: Arx is a direct target of Dlx2 and thereby contributes to the tangential migration of GABAergic interneurons.

  Gaia Colasante, Patrick Collombat, Valentina Raimondi, Dario Bonanomi, Carmelo Ferrai, Mario Maira, Kazuaki Yoshikawa, Ahmed Mansouri, Flavia Valtorta, John L R Rubenstein, Vania Broccoli
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  ABSTRACT: The Arx transcription factor is expressed in the developing ventral telencephalon and subsets of its derivatives. Mutation of human ARX ortholog causes neurological disorders including epilepsy, lissencephaly, and mental retardation. We have isolated the mouse Arx endogenous enhancer modules that control its tightly compartmentalized forebrain expression. Interestingly, they are scattered downstream of its coding region and partially included within the introns of the downstream PolA1 gene. These enhancers are ultraconserved noncoding sequences that are highly conserved throughout the vertebrate phylum. Functional characterization of the Arx GABAergic enhancer element revealed its strict dependence on the activity of Dlx transcription factors. Dlx overexpression induces ectopic expression of endogenous Arx and its isolated enhancer, whereas loss of Dlx expression results in reduced Arx expression, suggesting that Arx is a key mediator of Dlx function. To further elucidate the mechanisms involved, a combination of gain-of-function studies in mutant Arx or Dlx tissues was pursued. This analysis provided evidence that, although Arx is necessary for the Dlx-dependent promotion of interneuron migration, it is not required for the GABAergic cell fate commitment mediated by Dlx factors. Although Arx has additional functions independent of the Dlx pathway, we have established a direct genetic relationship that controls critical steps in the development of telencephalic GABAergic neurons. These findings contribute elucidating the genetic hierarchy that likely underlies the etiology of a variety of human neurodevelopmental disorders.
  Journal of Neuroscience 11/2008; 28(42):10674-86. · 7.11 Impact Factor
• Article: The homeobox gene Arx is a novel positive regulator of embryonic myogenesis.

  S Biressi, G Messina, P Collombat, E Tagliafico, S Monteverde, L Benedetti, M G Cusella De Angelis, A Mansouri, S Ferrari, S Tajbakhsh, V Broccoli, G Cossu
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  ABSTRACT: Skeletal muscle fibers form in overlapping, but distinct phases that depend on the generation of temporally different lineages of myogenic cells. During primary myogenesis (E10.5-E12.5 in the mouse), embryonic myoblasts fuse homotypically to generate primary fibers, whereas during later development (E14.5-E17.5), fetal myoblasts differentiate into secondary fibers. How these myogenic waves are regulated remains largely unknown. Studies have been hampered by the lack of markers which would distinguish embryonic from fetal myoblast populations. We show here that the homeobox gene Arx is strongly expressed in differentiating embryonic muscle, downstream of myogenic basic helix-loop-helix (bHLH) genes. Its expression progressively decreases during development. When overexpressed in the C2C12 myogenic cell line, Arx enhances differentiation. Accordingly, it stimulates the transcriptional activity from the Myogenin promoter and from multimerized E-boxes when co-expressed with MyoD and Mef2C in CH310T1/2. Furthermore, Arx co-immunoprecipitates with Mef2C, suggesting that it participates in the transcriptional regulatory network acting in embryonic muscle. Finally, embryonic myoblasts isolated from Arx-deficient embryos show a delayed differentiation in vivo together with an enhanced clonogenic capacity in vitro. We propose here that Arx acts as a novel positive regulator of embryonic myogenesis by synergizing with Mef2C and MyoD and by establishing an activating loop with Myogenin.
  Cell Death and Differentiation 02/2008; 15(1):94-104. · 8.85 Impact Factor
• Article: A Regulatory Path Associated with X-Linked Intellectual Disability and Epilepsy Links KDM5C to the Polyalanine Expansions in ARX.

  Loredana Poeta, Francesca Fusco, Denise Drongitis, Cheryl Shoubridge, Genesia Manganelli, Stefania Filosa, Mariateresa Paciolla, Monica Courtney, Patrick Collombat, Maria Brigida Lioi, Jozef Gecz, Matilde Valeria Ursini, Maria Giuseppina Miano
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  ABSTRACT: Intellectual disability (ID) and epilepsy often occur together and have a dramatic impact on the development and quality of life of the affected children. Polyalanine (polyA)-expansion-encoding mutations of aristaless-related homeobox (ARX) cause a spectrum of X-linked ID (XLID) diseases and chronic epilepsy, including infantile spasms. We show that lysine-specific demethylase 5C (KDM5C), a gene known to be mutated in XLID-affected children and involved in chromatin remodeling, is directly regulated by ARX through the binding in a conserved noncoding element. We have studied altered ARX carrying various polyA elongations in individuals with XLID and/or epilepsy. The changes in polyA repeats cause hypomorphic ARX alterations, which exhibit a decreased trans-activity and reduced, but not abolished, binding to the KDM5C regulatory region. The altered functioning of the mutants tested is likely to correlate with the severity of XLID and/or epilepsy. By quantitative RT-PCR, we observed a dramatic Kdm5c mRNA downregulation in murine Arx-knockout embryonic and neural stem cells. Such Kdm5c mRNA diminution led to a severe decrease in the KDM5C content during in vitro neuronal differentiation, which inversely correlated with an increase in H3K4me3 signal. We established that ARX polyA alterations damage the regulation of KDM5C expression, and we propose a potential ARX-dependent path acting via chromatin remodeling.
  The American Journal of Human Genetics 12/2012; · 10.60 Impact Factor
• Article: The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells.

  Patrick Collombat, Xiaobo Xu, Philippe Ravassard, Beatriz Sosa-Pineda, Sébastien Dussaud, Nils Billestrup, Ole D Madsen, Palle Serup, Harry Heimberg, Ahmed Mansouri
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  ABSTRACT: We have previously reported that the loss of Arx and/or Pax4 gene activity leads to a shift in the fate of the different endocrine cell subtypes in the mouse pancreas, without affecting the total endocrine cell numbers. Here, we conditionally and ectopically express Pax4 using different cell-specific promoters and demonstrate that Pax4 forces endocrine precursor cells, as well as mature alpha cells, to adopt a beta cell destiny. This results in a glucagon deficiency that provokes a compensatory and continuous glucagon+ cell neogenesis requiring the re-expression of the proendocrine gene Ngn3. However, the newly formed alpha cells fail to correct the hypoglucagonemia since they subsequently acquire a beta cell phenotype upon Pax4 ectopic expression. Notably, this cycle of neogenesis and redifferentiation caused by ectopic expression of Pax4 in alpha cells is capable of restoring a functional beta cell mass and curing diabetes in animals that have been chemically depleted of beta cells.
  Cell 09/2009; 138(3):449-62. · 32.40 Impact Factor