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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 U54 Center Grant, as part of the NICHD "Specialized Co-operative Centers Program in Reproduction". 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. Led by Dr. Kim Holloway, these studies are aimed at understanding the role of the FA network in germ cell proliferation and genome maintenance in primordial germ cells. 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.

 

IN THE NEWS ....

Recent Publications

Welcome to Kate!

We would like to extend a hearty welcome to our new Postdoctoral Fellow, Dr. Kate Grive, who arrived here in December from Brown University, where she completed her PhD with Rich Freiman.

 

Our new publication reveals a role for FANCJ in crossover regulation

A new paper in Chromosoma reveals a role for FANCJ (or BRIP1), a BRCA1-associated helicase, in modulating rates of MLH1 association with Double strand break repair sites during mammalian meiosis. FANCJ also appears critical for normal spermatogonial cell proliferation during embryonic development.  See our publications for more information.

 

First Cohen Lab Annual Retreat held in November 2015

The first Cohen Lab retreat was held in November at the Nevin Center of the Cornell Plantations.  All members of the lab were present for a day of talks and stimulating discussion.  We would like to thank Steve and Miguel for organizing a really fun and informative day!!!

 

Farewell to Kadeine

Congratulations to Kadeine Campbell-Peterson who recently moved on from the lab to accept a teaching position in New York City.  We wishe her the best of luck in all her future career endeavors!