Bio

Bio


I am a postdoc in Anne Villeneuve's lab in the Department of Developmental Biology working on meiosis and recombination in C.elegans. I am mostly interested in how recombination is regulated to ensure genome stability. I previously conducted a PhD thesis at INRA de Versailles (France) under the direction of RaphaŽl Mercier on new genes controlling meiotic recombination level in Arabidopsis. I am interested in genetics, epigenetics, evolution but also in popularization of science.

Honors & Awards


  • Young Researcher Prize, Bettencourt-Schueller Foundation (2015)
  • "CJS? PhD Grant recipient, for a 3-year PhD thesis and a 2-year postdoctoral program, French National Institute for Agricultural Research (10/2011)

Boards, Advisory Committees, Professional Organizations


  • Co-organizer, Bay Area Worm Meeting (2016 - 2016)
  • Volunteer - Teacher Recruitment, Stanford SPLASH (2016 - 2017)
  • Co-organizer, Bi-weekly research forum of the C. elegans groups at Stanford (2016 - Present)

Professional Education


  • PhD, Universite Paris Sud (Orsay, France), Biology (2014)
  • Master of Science, Universite Paris Sud (Orsay, France), Plant Biology (2011)
  • Master of Science, AgroParisTech (Paris, France), Agronomy (2011)

Stanford Advisors


Community and International Work


  • Screening to decipher meiosis in C. elegans

    Topic

    Recombination, Meiosis

    Partnering Organization(s)

    Stanford University

    Location

    California

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

Patents


  • Mercier R., Girard C., Crismani W. - Froger N.. "France Patent WO2015001467 A1 Increased meiotic recombination in plants by inhibition of the fidg protein", INRA, Jan 8, 2015
  • Mercier R., Crismani W. - Girard, C., Froger N.. "United States Patent US20140289902 A1/ WO2013038376A1 Increase in meiotic recombination in plants by inhibiting the fancm protein", INRA, Sep 25, 2014

Research & Scholarship

Current Research and Scholarly Interests


Meiotic crossovers (COs) are critical for the balanced segregation of homologous chromosomes at meiosis I. Crossover recombination events between DNA molecules of homologous chromosomes, together with sister chromatid cohesion, establish a physical connection between homologs (chiasmata), which in turn ensures their correct orientation toward oppotiste poles of the meiosis I spindle.

Crossover (CO) formation at meiosis relies on the formation and repair of numerous double-strand DNA breaks (DSBs). Most species make very few COs per chromosome pair despite a substantial excess of DSBs, and C.elegans stands at one hand of this spectrum with one, and only one, CO formed per chromosome pair. We are using direct genetic screening approaches to elucidate and decipher the mechanisms underlying meiotic CO formation and its regulation.

Our goal is to identify factors that normally function in antagonizing CO formation; as part of our strategy, we are conducting a genetic screen for suppressors of a temperature-sensitive mutation affecting the conserved CO-promoting complex MSH-4/MSH-5. The msh-4(ts) mutant is characterized by a decrease in CO formation at the restrictive temperature of 24įC, associated with a small brood size. We will report on the first 4 suppressor lines identified with a clear rescue of the progeny viability and number of CO per meiosis.

Lab Affiliations


Publications

All Publications


  • Interdependent and separable functions of Caenorhabditis elegans MRN-C complex members couple formation and repair of meiotic DSBs PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Girard, C., Roelens, B., Zawadzki, K. A., Villeneuve, A. M. 2018; 115 (19): E4443?E4452

    Abstract

    Faithful inheritance of genetic information through sexual reproduction relies on the formation of crossovers between homologous chromosomes during meiosis, which, in turn, relies on the formation and repair of numerous double-strand breaks (DSBs). As DSBs pose a potential threat to the genome, mechanisms that ensure timely and error-free DSB repair are crucial for successful meiosis. Here, we identify NBS-1, the Caenorhabditis elegans ortholog of the NBS1 (mutated in Nijmegen Breakage Syndrome) subunit of the conserved MRE11-RAD50-NBS1/Xrs2 (MRN) complex, as a key mediator of DSB repair via homologous recombination (HR) during meiosis. Loss of nbs-1 leads to severely reduced loading of recombinase RAD-51, ssDNA binding protein RPA, and pro-crossover factor COSA-1 during meiotic prophase progression; aggregated and fragmented chromosomes at the end of meiotic prophase; and 100% progeny lethality. These phenotypes reflect a role for NBS-1 in processing of meiotic DSBs for HR that is shared with its interacting partners MRE-11-RAD-50 and COM-1 (ortholog of Com1/Sae2/CtIP). Unexpectedly, in contrast to MRE-11 and RAD-50, NBS-1 is not required for meiotic DSB formation. Meiotic defects of the nbs-1 mutant are partially suppressed by abrogation of the nonhomologous end-joining (NHEJ) pathway, indicating a role for NBS-1 in antagonizing NHEJ during meiosis. Our data further reveal that NBS-1 and COM-1 play distinct roles in promoting HR and antagonizing NHEJ. We propose a model in which different components of the MRN-C complex work together to couple meiotic DSB formation with efficient and timely engagement of HR, thereby ensuring crossover formation and restoration of genome integrity before the meiotic divisions.

    View details for PubMedID 29686104

  • RMI1 and TOP3 alpha limit meiotic CO formation through their C-terminal domains NUCLEIC ACIDS RESEARCH Seguela-Arnaud, M., Choinard, S., Larcheveque, C., Girard, C., Froger, N., Crismani, W., Mercier, R. 2017; 45 (4): 1860-1871
  • AAA-ATPase FIDGETIN-LIKE 1 and Helicase FANCM Antagonize Meiotic Crossovers by Distinct Mechanisms PLOS GENETICS Girard, C., Chelysheva, L., Choinard, S., Froger, N., Macaisne, N., Lehmemdi, A., Mazel, J., Crismani, W., Mercier, R. 2015; 11 (7)

    Abstract

    Meiotic crossovers (COs) generate genetic diversity and are critical for the correct completion of meiosis in most species. Their occurrence is tightly constrained but the mechanisms underlying this limitation remain poorly understood. Here we identified the conserved AAA-ATPase FIDGETIN-LIKE-1 (FIGL1) as a negative regulator of meiotic CO formation. We show that Arabidopsis FIGL1 limits CO formation genome-wide, that FIGL1 controls dynamics of the two conserved recombinases DMC1 and RAD51 and that FIGL1 hinders the interaction between homologous chromosomes, suggesting that FIGL1 counteracts DMC1/RAD51-mediated inter-homologue strand invasion to limit CO formation. Further, depleting both FIGL1 and the previously identified anti-CO helicase FANCM synergistically increases crossover frequency. Additionally, we showed that the effect of mutating FANCM on recombination is much lower in F1 hybrids contrasting from the phenotype of inbred lines, while figl1 mutation equally increases crossovers in both contexts. This shows that the modes of action of FIGL1 and FANCM are differently affected by genomic contexts. We propose that FIGL1 and FANCM represent two successive barriers to CO formation, one limiting strand invasion, the other disassembling D-loops to promote SDSA, which when both lifted, leads to a large increase of crossovers, without impairing meiotic progression.

    View details for DOI 10.1371/journal.pgen.1005369

    View details for Web of Science ID 000360622200034

    View details for PubMedID 26161528

  • FANCM-associated proteins MHF1 and MHF2, but not the other Fanconi anemia factors, limit meiotic crossovers NUCLEIC ACIDS RESEARCH Girard, C., Crismani, W., Froger, N., Mazel, J., Lemhemdi, A., Horlow, C., Mercier, R. 2014; 42 (14): 9087-9095

    Abstract

    Genetic recombination is important for generating diversity and to ensure faithful segregation of chromosomes at meiosis. However, few crossovers (COs) are formed per meiosis despite an excess of DNA double-strand break precursors. This reflects the existence of active mechanisms that limit CO formation. We previously showed that AtFANCM is a meiotic anti-CO factor. The same genetic screen now identified AtMHF2 as another player of the same anti-CO pathway. FANCM and MHF2 are both Fanconi Anemia (FA) associated proteins, prompting us to test the other FA genes conserved in Arabidopsis for a role in CO control at meiosis. This revealed that among the FA proteins tested, only FANCM and its two DNA-binding co-factors MHF1 and MHF2 limit CO formation at meiosis.

    View details for DOI 10.1093/nar/gku614

    View details for Web of Science ID 000343219200028

    View details for PubMedID 25038251

  • Tinkering with meiosis JOURNAL OF EXPERIMENTAL BOTANY Crismani, W., Girard, C., Mercier, R. 2013; 64 (1): 55-65

    Abstract

    Meiosis is at the heart of Mendelian heredity. Recently, much progress has been made in the understanding of this process, in various organisms. In the last 15 years, the functional characterization of numerous genes involved in meiosis has dramatically deepened our knowledge of key events, including recombination, the cell cycle, and chromosome distribution. Through a constantly advancing tool set and knowledge base, a number of advances have been made that will allow manipulation of meiosis from a plant breeding perspective. This review focuses on the aspects of meiosis that can be tinkered with to create and propagate new varieties. We would like to dedicate this review to the memory of Simon W. Chan (1974-2012) (http://www.plb.ucdavis.edu/labs/srchan/).

    View details for DOI 10.1093/jxb/ers314

    View details for Web of Science ID 000312651100004

    View details for PubMedID 23136169

  • OSD1 Promotes Meiotic Progression via APC/C Inhibition and Forms a Regulatory Network with TDM and CYCA1;2/TAM PLOS GENETICS Cromer, L., Heyman, J., Touati, S., Harashima, H., Araou, E., Girard, C., Horlow, C., Wassmann, K., Schnittger, A., De Veylder, L., Mercier, R. 2012; 8 (7)

    Abstract

    Cell cycle control is modified at meiosis compared to mitosis, because two divisions follow a single DNA replication event. Cyclin-dependent kinases (CDKs) promote progression through both meiosis and mitosis, and a central regulator of their activity is the APC/C (Anaphase Promoting Complex/Cyclosome) that is especially required for exit from mitosis. We have shown previously that OSD1 is involved in entry into both meiosis I and meiosis II in Arabidopsis thaliana; however, the molecular mechanism by which OSD1 controls these transitions has remained unclear. Here we show that OSD1 promotes meiotic progression through APC/C inhibition. Next, we explored the functional relationships between OSD1 and the genes known to control meiotic cell cycle transitions in Arabidopsis. Like osd1, cyca1;2/tam mutation leads to a premature exit from meiosis after the first division, while tdm mutants perform an aberrant third meiotic division after normal meiosis I and II. Remarkably, while tdm is epistatic to tam, osd1 is epistatic to tdm. We further show that the expression of a non-destructible CYCA1;2/TAM provokes, like tdm, the entry into a third meiotic division. Finally, we show that CYCA1;2/TAM forms an active complex with CDKA;1 that can phosphorylate OSD1 in vitro. We thus propose that a functional network composed of OSD1, CYCA1;2/TAM, and TDM controls three key steps of meiotic progression, in which OSD1 is a meiotic APC/C inhibitor.

    View details for DOI 10.1371/journal.pgen.1002865

    View details for Web of Science ID 000306840400057

    View details for PubMedID 22844260

  • FANCM Limits Meiotic Crossovers SCIENCE Crismani, W., Girard, C., Froger, N., Pradillo, M., Luis Santos, J., Chelysheva, L., Copenhaver, G. P., Horlow, C., Mercier, R. 2012; 336 (6088): 1588-1590

    Abstract

    The number of meiotic crossovers (COs) is tightly regulated within a narrow range, despite a large excess of molecular precursors. The factors that limit COs remain largely unknown. Here, using a genetic screen in Arabidopsis thaliana, we identified the highly conserved FANCM helicase, which is required for genome stability in humans and yeasts, as a major factor limiting meiotic CO formation. The fancm mutant has a threefold-increased CO frequency as compared to the wild type. These extra COs arise not from the pathway that accounts for most of the COs in wild type, but from an alternate, normally minor pathway. Thus, FANCM is a key factor imposing an upper limit on the number of meiotic COs, and its manipulation holds much promise for plant breeding.

    View details for DOI 10.1126/science.1220381

    View details for Web of Science ID 000305507500060

    View details for PubMedID 22723424

  • The CYCLIN-A CYCA1;2/TAM Is Required for the Meiosis I to Meiosis II Transition and Cooperates with OSD1 for the Prophase to First Meiotic Division Transition PLOS GENETICS d'Erfurth, I., Cromer, L., Jolivet, S., Girard, C., Horlow, C., Sun, Y., To, J. P., Berchowitz, L. E., Copenhaver, G. P., Mercier, R. 2010; 6 (6)

    Abstract

    Meiosis halves the chromosome number because its two divisions follow a single round of DNA replication. This process involves two cell transitions, the transition from prophase to the first meiotic division (meiosis I) and the unique meiosis I to meiosis II transition. We show here that the A-type cyclin CYCA1;2/TAM plays a major role in both transitions in Arabidopsis. A series of tam mutants failed to enter meiosis II and thus produced diploid spores and functional diploid gametes. These diploid gametes had a recombined genotype produced through the single meiosis I division. In addition, by combining the tam-2 mutation with AtSpo11-1 and Atrec8, we obtained plants producing diploid gametes through a mitotic-like division that were genetically identical to their parents. Thus tam alleles displayed phenotypes very similar to that of the previously described osd1 mutant. Combining tam and osd1 mutations leads to a failure in the prophase to meiosis I transition during male meiosis and to the production of tetraploid spores and gametes. This suggests that TAM and OSD1 are involved in the control of both meiotic transitions.

    View details for DOI 10.1371/journal.pgen.1000989

    View details for Web of Science ID 000279805200018

    View details for PubMedID 20585549

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