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Studies of mammalian germ cell development and meiosis

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  • Meiotic Recombination
  • Small RNAs in Recombination
  • Fanconi Anemia
  • MAPK
    Signaling
  • NEK1
    Kinase

The Cohen lab has been instrumental in defining the role of the DNA mismatch repair (MMR) pathway in mammalian meiosis. Using mouse mutants for each of the mammalian MMR orthologs, we have determined that MSH4/MSH5 heterodimers recruit MLH1/MLH3 to class I crossover sites in order to specify the appropriate number and spacing of crossover events in the mammalian genome.

Our continued research in this area focuses on how these crossover mediators of the class I pathway interact with mediators of the class II pathway, through recruitment and integration via key helicases and endonucleases such as BLM, EXO1, and SLX4. In addition, we are currently investigating the role of the cyclin n-terminal domain containing protein-1 (CNTD1) in controlling class I crossing over. For more details click on image.

Small RNAs are known to be important regulators of germ cell development, primarily through the action of the germline-specific PIWI-interacting, or piRNAs. Recently, our lab has explored the role of the Argonaute family of small RNA binding proteins, focussing specifically on the class of Argonautes that are specific to microRNA and endosiRNA species, but which do not interact with the piRNAs.

Our data demonstrate that AGO4 binds microRNAs in mammalian germ cells and that this interaction is important for numerous aspects of germ cell development, particularly in meiosis. Our continued studies in this area are aimed at understanding how AGO4 and its RNA binding partners mediate essential events during prophase I and beyond in the mouse. These studies formed the basis for our recently awarded P50 Center Grant, as part of the NICHD "National Centers for Research in Reproduction and Infertility (NCTRI)". For more details click on image.

While studying proteins that may influence meiotic crossing over in the mouse, we became interested in the newest member of the Fanconi Anemia pathway, SLX4 or FANCP. SLX4 interacts with key components of the recombinogenic machinery in mammals and, as such, is well placed to regulate cross over pathways as described elsewhere in this website.

In addition to its role in meiotic recombination, we are also investigating the role of the Fanconi network as a whole, but FANCP/SLX4 more specifically, in germ cell development. We recently generated a mouse mutant for the FA gene, FANCJ (BRIP1), and demonstrated a role for this gene in germ cell proliferation and in orchestrating events during Prophase I. Ongoing studies in collaboration with the labs of Marcus Smolka and Bob Weiss are aimed at elucidating how FANCJ functions in the context of the ATM/ATR kinase cascade. For more details click on image.

 

The extracellular signal regulated kinases, ERK1 and ERK2, play important roles in signaling downstream of hormones and growth factors. In ovarian cumulus cells, the ERKs are essential for mediating key events during folliculogenesis that ultimately facilitate ovulation. Studies in conjunction with the lab of Dr. Mark Roberson are ongoing to explore the role of the ERKs in meiotic prophase I and in events specifically within the oocyte of the adult ovary. For more details click on image.

 

The NIMA-like kinase, NEK1, is a member of a large family of serine threonine kinases that is unique amongst its family members in that it also encodes tyrosine kinase activity. We became interested in NEK1 when we discovered an important interaction between NEK1 and two SC components: SYCP1 and FKBP6. More recently we have identified a key role for NEK1 in removal of key cohesin components at the end of prophase I in mouse spermatocytes (Holloway et al, 2011). Studies are ongoing to identify the exact molecular mechanisms by which NEK1 participates in these events. Specifically, we have identified a novel mechanism by which NEK1 controls components of the Prophse Pathway via interactions with PDS5B, WAPL and Sororin. See our recent publication for more details.

 

IN THE NEWS ....

Recent Publications

Two NIH K99 Awards for the Cohen Lab

Congratulations to Dr. Miguel Brieno-Enriquez and Dr. Steve Gray, who are each new recipients of a K99 Career Transition Award from NICHD. Miguel's application extend from his recently published studies defining the role of NEK1 in the prophase pathway that orchestrates cohesin removal during meiosis. Steve's K99 grant focused on novel approaches for understanding the role of cyclin-dependent kinases in prophase I. Both awards are due to begin in 2017. We are exceptionally proud of both Miguel and Steve, particularly in attaining one of these highly competitive awards!



 

Cohen Lab receives Gates Foundation Grant

The Lab recently won a Grand Challenges Explorations Grant from the Bill and Melinda Gates Foundation. This grant wil fund research into development of a contraceptive platform for identifying new drug targets in spermatogenesis. The Explorations phase provides seed funding for the initial idea. Only upon successful completion of this phase can the lab then apply for the full funding. For further details, see the article in the Cornell Chronicle


Congraulations to Dr. Toledo !

Congratulations to Mellissa Toledo, who successfully funded her thesis in May and will be walking in the 2017 May Cornell Commencement. Melissa is currently finishing off one manuscript and wrapping up experiments for a second before she heads off to NYC to take up a position at a private IVF clinic as an Embryologist in training. Best of luck Melissa, and make sure you come back and visit us!

 

Congratulations to Adriana

 

Congratulations to our new graduate student, Adriana Alexander, who was recently awarded a graduate fellowship from the NSF for her studies to elucidate the roles of the Argonaute proteins in meiotic silencing. Adriana will be a joint graduate student between our lab and the lab of Charles Danko to study promoter-enhancer interactions in the mammalian germ lineage.