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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

Congraulations to Steve!

Congratulations to Dr. Steve Gray, for his recent publication in Annual Review of Genetics. In this article, Steve explores the recent advances in our understanding of how crossovers are regulated across eukaryotic species. He highlights key differences between species, while at the same time providing some clarity on the conserved mechanisms observed during meiotic prophase I. See our recent publications for more information.

 

New publication sheds light on the mechanisms of cohesin removal in meiosis I

Our new manuscript, published in the October 18th issue of Cell Reports, describes work to elucidate the role of the NIMA-like kinase, NEK1 in mammalian meiosis. Loss of NEK1 leads to hyperphosphorylation of WAPL, a component of the Prophase Pathway, leading to premature removal of WAPL and persistence of its antagonistic partner, Sororin. Together, this restricts cohesin loss after prophase I. Congratulations to Dr. Kim Holloway, lead author on this paper, and Dr. Miguel Brieno-Enriquez, first author, for all their hard work! Thanks too to the many contributors.

 

Congraulations to Miguel!

Congratulations to Postdoctoral Fellow, Dr. Miguel Brieno-Enriquez, who was recently appointed onto the New York Stem Cell Program (NYSTEM) training grant, headed by Dr. Alex Nikitin. Miguel will be studying early primordial germ cell progression into the oocyte lineages in mouse and human. Miguel has had a particularly exciting month, with the training grant appointment, his invitation to present his work at the Cold Spring Harbor Germ Cell Meeting, and with the recent acceptance of his paper into Cell Reports (above)

 

Welcome Adriana

Welcome to our new graduate student, Adriana Alexander, who has joined us as part of the BBS Graduate Program. Adriana will be working on the role of Argonaute proteins in meiotic silencing.