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Non-coding RNA pathways and the mammalian male germline

Non-coding RNA pathways and the mammalian male germline

Objective

The integrity of the genome transmitted to the next generation intrinsically relies on germline cells. Processes ensuring germ cell development, genomic stability and reproductive lifespan are essential for the long-term success of a species. Spermatogonial stem cells (SSCs) support spermatogenesis throughout life, the identity of this mammalian adult stem cell population in vivo remains unknown. Here, we propose analyze the contribution of both short and long non-coding RNAs to mammalian male germ cell development and SSC homeostasis. In the mouse male germline the small non-coding piRNAs and their interacting-Piwi proteins Mili and Miwi2 are essential for the establishment of epigenetic transposon silencing. Miwi2 is also required for the long-term survival of SSCs in adult mice and in contrast to Mili, Miwi2 is not broadly expressed during adult spermatogeneis. We found that Miwi2 is expressed in in vitro cultured SSCs and in a tiny population of adult testis cells in vivo. We will determine if Miwi2 expression identifies the illusive SSC population with long-term self-renewal capacity in vivo and explore the biology of this adult stem cell population as well as the molecular mechanisms by which the Miwi2-piRNA pathway governs SSC maintenance. We will also define function(s) beyond transposon silencing for Mili during spermatogenesis. Recently, transcriptome sequencing has reveled abundant and diverse classes of genes encoding long non-coding RNAs (lncRNAs) whose functions remains mostly unknown. We will explore the contribution this novel class of cellular RNAs in SSC self-renewal and differentiation. For the above, we propose using state-of-the-art mouse genetic strategies, high throughput sequencing, shRNA screening and proteomic approaches. In summary, this proposal aims to address basic questions at the intersection of non-coding RNA function and germ cell development/maintenance to reveal processes that underpin the integrity of the immortal lineage.
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Principal Investigator

Dόnal O'carroll (Dr.)

Host institution

THE UNIVERSITY OF EDINBURGH

Address

Old College, South Bridge
Eh8 9yl Edinburgh

United Kingdom

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 784 760,11

Principal Investigator

Dόnal O'carroll (Dr.)

Administrative Contact

Alan Kennedy (Mr.)

Beneficiaries (2)

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THE UNIVERSITY OF EDINBURGH

United Kingdom

EU Contribution

€ 784 760,11

EUROPEAN MOLECULAR BIOLOGY LABORATORY

Germany

EU Contribution

€ 714 317,89

Project information

Grant agreement ID: 310206

Status

Closed project

  • Start date

    1 January 2013

  • End date

    31 December 2017

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 1 499 078

  • EU contribution

    € 1 499 078

Hosted by:

THE UNIVERSITY OF EDINBURGH

United Kingdom