PAX7 TRANSGENICS · Conditional inactivation of Notch signalling during myogenesis by development and application of Pax7 specific transgenic mouse models
6РП — Действия „Мария Кюри“
- Период
- 2007-05-01 → 2009-04-30
- Финансиране от ЕС
- 92 671 €
- Участници
- 1
- Схема
- IIF
Линиите свързват координатора с партньорите.
Накратко на български
Генните механизми при развитието на мускулите и гръбнака се анализират чрез създаване на трансгенни мишки. Това помага за разбирането на процесите по изграждане на тялото и причините за развитието на миопатии.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - PAX7 TRANSGENICS (Conditional inactivation of Notch signalling during myogenesis by development and application of Pax7 specific transgenic mouse models)
This project has incorporated several project foci so as to maximize output in the 2 year fellowship period. This work can be grouped into two categories. Firstly, relating to Hox gene regulation of axial elongation and secondly relating to aspects of myogenesis and disorders associated with myogenesis. With relation to Hox gene regulation of axial elongation, we have created transgenic mouse models to demonstrate that HoxC13 is able to impair axial elongation by impairment of Wnt and retinoic acid signaling without any observable impact on GDF signaling. FGF signaling is mildly impaired with overexpression of HoxC13 in mouse embryo presomitic mesoderm. This work is in review for Developmental Cell in a collaborative paper with Jacqueline Deschamps from the Hubrecht Institute in Holland, and a second manuscript is in preparation to publish additional data generated from this project. Relating to myogenesis investigation, two main avenues of investigation have been and continue to be underway. Firstly, we have been generating transgenic models for Pax7-Cre, and Pax7-RTTA in order to specifically delete floxed genes downstream of Pax7. Secondly, we have generated a targeted ES cell line to specifically ablate GNE in Cre expressing cell lines. GNE is the gene that when mutated is responsible for Heterologous Inclusion Body Myopathy. We are currently breeding chimeric mice generated from these ES cells and will investigate the impact of tissue specific deletions on myogenesis. This work has been funded additionally by the Association for Research Myopathies.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Determination of the complex cause and effect signalling pathways that lead from pluripotent precursor cells to differentiated tissue is a critical topic that impacts on the development of effective stem cell therapies. Notch signalling is important for many cell fate decisions, however for myogenic progenitors clear genetic proof is still required.Because Notch mutants are embryonic lethal, we aim to develop a conditional inactivation system utilising Cre/lox murine transgenesis. We will introduce Cre recombinase expression under control of native Pax7 control elements as this gene defines the embryonic myogenic lineage and adult muscle satellite cells.We will also use the Tet-On system to allow temporal control of Cre-mediated recombination. By crossing these Cre-expressing lines with mice carrying floxed alleles of Notch1 and its downstream effector RBPJk, we will be able to inactivate these genes in embryonic myogenic precursors and adult muscle satellite cells.Whilst this transgenic approach is underway we will also conduct a collaborative in vitro side project whereby protein extract from cultured in vitro myoblasts are affinity captured to identify interactors for a previously identified critical E-box transcriptional binding site located in the Myf5 promoter.Overall, our transgenic approach will provide the means to determine the role of Notch signalling in myogenic precursor cell development in the embryo and adult.The Pax7 specific Cre expressing transgenics will also provide a tool that we will be able to apply to other gene targets in myogenesis, which will help resolve the pathways essential to myogenic cell fate determination. Additionally, we will be investigating potential new regulators of Myf5 in vitro.
Оригинален текст от CORDIS (на английски).
Участници
- FUNDAÇÃO CALOUSTE GULBENKIAN · LISBOAКоординаторПортугалия
Връзки
Данни: CORDIS, © Европейски съюз