Dr. John Schimenti

The important roles of microRNAs (miRNAs) in almost all aspects of genome regulation and organismal biology have become appreciated in the past decade, and methods to probe their functions have become routine in invertebrate models and in mammalian cell culture paradigms. However, functional studies of miRNAs in mammalian gametogenesis have lagged due to the physiological complexities of this process and the lack of suitable in vitro systems. Our project seeks to develop technologies to query the function and targets of virtually all conserved miRNAs that are expressed during mouse and human spermatogenesis.  One strategy to identify the bona-fide gene targets of all conserved, male germ cell-expressed miRNAs involves the creation of a comprehensive and flexible set of combinatorial transgenic mice bearing miRNA arrays, followed by RNA-seq analysis of the transgenic lines to identify the in vivo targets of the miRNAs. The second strategy is to ablate miRNAs, then use RNA-seq to identify mRNAs or proteins that increase in abundance. Towards this end, we are using CRISPR-mediated mutagenesis to simultaneously knockout multiple miRNAs in mouse embryos. If successful, this would be readily scalable to all miRNAs of interest in the germline.  Ultimately, the success of either strategy will allow us to deduce the roles of small RNAs in male fertility.

Lab personnel working on this project include Kerry Schimenti and Vera Rinaldi.

Recent Publications in the area of Reproduction include:

  1. Hartford, S. Luo, Y., Southard, T., Min, I., Lis, J. and Schimenti, J. (2011) Minichromosome maintenance helicase paralog MCM9 is dispensible for DNA replication but functions in germline stem cells and tumor suppression.  PNAS 108:17702-7. PMCID:PMC3203795
  2. Fukuda, T., Pratto, F., Schimenti, J., Turner, J., Camerini-Otero, D. and Hoog, C. (2012) Phosphorylation of chromosome core components may serve as axis marks for the status of chromosomal events during mammalian meiosis. PLoS Genetics, 8(2):e1002485 PMC3276554.
  3. Su, Y-Q, Sugiura, K., Sun, F., Pendola, J., Cox, G., Handel, MA., Schimenti, J. and Eppig, J.  (2012) MARF1 regulates essential oogenic processes in mice.  Science, 335:1496-9.
  4. Bolcun-Filas, E. and Schimenti, J. (2012) Genetics of meiosis and recombination in mice. Intl. Rev. Cell & Molecular Biology 298:179-227.
  5. Flachs, P., Mihola, O., Simecek, P., Gregorova, S., Schimenti, J., Matsui, Y., Baudat, F., de Massy, B., Pialek, J., Forejt, J. and Trachtulec, Z. (2012) Interallelic and intergenic incompatibilities of the Hst1/Prdm9 gene in mouse hybrid sterility.  PLoS Genetics 8:e1003044. doi/pgen.1003044.
  6. Su, Y-Q, Sun, F., Handel, MA, Schimenti, J and Eppig J. (2012) MARF1 has nuage-like function in mammalian oocytes. PNAS 109:18653-60. PMC3503166.
  7. Li, X., Roy, C., Dong, X., Bolcun-Filas, E., Wang, J., Han, B., Xu, J., Moore, M.,  Schimenti, J., Weng, Z., and Zamore, P. (2013) An ancient transcription factor initiates the burst of piRNA production during meiosis in the mouse testis.  Molecular Cell 50:67-81.
  8. Schimenti, K., Feuer, S., Griffin, L., Graham, N., Bovet, C., Hartford, S., Pendola, J., Lessard, C.,  Schimenti, J. and Ward, J.  (2013) AKAP9 is vital for spermatogenesis and Sertoli cell maturation in mice. Genetics 194: 447-457.
    Bolcun-Filas, E., White, M., Rinaldi, V. and Schimenti, J. Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint. (2014) Science, 343:533-536.
  9. Qiao, H., Rao, H., Yang, Y., Fong, J., Cloutier, J., Dekker, D., Nagel, K., Swartz, R., Strong, E., Holloway, K., Cohen, P., Schimenti, J., Ward, J. and Hunter, N.  Antagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination. (2014) Nature Genetics, 46:194-199.  PMID: 24390283.
  10. Harris, T., Schimenti, K., Munroe, R. and Schimenti, J. IQ motif-containing G (Iqcg) is required for mouse spermiogenesis. (2014) G3: Genes, Genome, Genetics 4:367-372. doi:10.1534/g3.113.009563. PMID: 24362311.
  11. Ishiguro, K,  Kim, J,  Shibuya,H,  Hernández-Hernández, A,  Suzuki, A,  Fukagawa, T, Shioi, G, Kiyonari, H,  Li, X., Schimenti, J,  Hoog, C and Watanabe, Y.  Meiosis-specific cohesin mediates homolog recognition in mouse spermatocytes. (2014)  Genes & Devel. 28:594-607.
  12. Cheng CY, Hwang CI, Corney DC, Flesken-Nikitin A, Jiang L, Oner GM, Munroe RJ, Schimenti JC, Hermeking H, Nikitin AY.  miR-34 Cooperates with p53 in Suppression of Prostate Cancer by Joint Regulation of Stem Cell Compartment. (2014) Cell Rep. 6:1000-1007.
  13. Luo, Y., Hartford, S., Zheng, R., Southard, T., Shima, N., and Schimenti, J. Hypersensitivity of primordial germ cells to compromised replication-associated DNA repair involves ATM-p53-p21 signaling.  (2014) PLoS Genetics,10:e1004471.
  14. Handel, MA, Eppig, J. and Schimenti, J.  Applying gold standards to in vitro-derived germ cells. (2014) Cell, 157:1257-61.

For more information on Dr. Schimenti's research, please see his lab website.

CRG News

Grimson and Cohen Labs identify critical regulatory pathways involving non-coding RNAs in sex body integrity during meiosis

A new study from Andrew Grimson's lab, in collaboration with Paula Cohen's lab, has identified a key pathway required for maintenance of sex chromosome telomere integrity. Using conditional knockout mice for Dicer and Dgcr8, two key enzymes required for small RNA processing, Modzelewski et al (2015) show that loss of small RNAs during prophase I leads to telomere fusion events specifically involving the X and Y chromosomes. For further information, see the May edition of Journal of Cell Science

Paduch Lab identifies critical Sertoli Cell-Germ cell interactions in human testis

A recent publication by Dabaja et al (2015) has identified key cell:cell interactions that are necessary to establish normal profiles of one key microRNA, miR202-5p, in Sertoli cells. This is the first example of a germ cell regulatory interaction that is necessary for miR expression in neighboring somatic cells of the testis

Six Postdoctoral Fellows awarded CRG seed grants
Six outstanding postdoctoral fellows have been awarded seed grants of between $5000 and $10,000 to initiate studies of non-coding RNAs in reproduction. All six projects have a firmly translational basis, and range from identification of long non-coding RNAs in meiosis, to establishing mechanisms by which small non-coding RNAs regulate estrogen production in the ovary. Funds will support experimental studies and use of the RNA Sequencing Core for up to one year.
Annual CRG symposium attracts researchers from over 15 institutions to Ithaca!
The CRG Annual Symposium was held in April, 2016, concurrent with the meeting of the NICHD Male Research Focus Group Meeting on the Ithaca campus of Cornell University. Over 150 participants from two Cornell campuses, along with guests from across the country, and researchers from neighboring institutions assembled together for this 2-day event. Prizes were awarded for the best trainee poster and oral presentation. For photos and coverage, click here.
Schimenti Lab sheds light on DNA damage checkpoint regulation in mammalian oocytes

The lab of Center member John Schimenti  recently identified the DNA damage checkpoint pathway responsible for culling oocytes that fail to repair double stranded breaks (DSBs) that occur during meiosis or which arise in a female's oocyte pool (Bolcun-Filas et al, Science 343:533-536, 2014).  Using combinations of mutants involved in recombination and DNA damage responses, they found that this pathway involves signaling of checkpoint kinase 2 (CHK2) to both p53 and p63. Disruption of this checkpoint pathway restored fertility to females that normally would be deficient of all oocytes due to defects in meiotic recombination or exposure to radiation. This discovery opens the way to using available CHK2 inhibitors to protect the oocytes of women undergoing cancer therapy that would normally cause infertility.