GLI3 LIMB PATTERNING · Setting-up a patterning system: the regulation and temporal changes in functioning of the transcriptional regulator GLI3 during mouse limb bud development
6РП — Действия „Мария Кюри“
- Период
- 2006-09-01 → 2008-08-31
- Финансиране от ЕС
- 184 590 €
- Участници
- 1
- Схема
- EIF
Линиите свързват координатора с партньорите.
Накратко на български
Регулаторът GLI3 контролира развитието на крайниците при мишките, като например определя броя на пръстите. Разбирането на този механизъм помага да се обяснят вродените малформации и появата на някои тумори при хората.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - GLI3 LIMB PATTERNING (Setting-up a patterning system: the regulation and temporal changes in functioning of the transcriptional regulator gli3 ...)
Sonic hedgehog (SHH) is a secreted protein used by embryonic and adult cells in tissues and organs to communicate by transmitting information concerning e.g. position and identity and to regulate their proliferation and differentiation. Its functions have been best studied in the context of the central nervous system (CNS) and limb organogenesis, where SHH is essential for pattern formation and proliferation. In the limb bud, SHH is involved in the establishment of anterior-posterior axis, which controls the correct development of ulna and radius and the formation of five digits (fingers and toes). Alterations of the SHH pathway cause severe congenital malformations including cyclopia and loss of hands and feet. Furthermore, aberrant, postnatal activation of the SHH pathway underlies a large variety of tumours in humans possibly due to inappropriate SHH-mediated stimulation of cell proliferation and/or altered differentiation states. To ensure that cells do not activate SHH signal transduction and expression of targets in the absence of the SHH ligand, there is cellular gatekeepers that block activation of signal transduction without a cell being exposed to the SHH ligand. The GLI3 transcriptional regulator is such a gatekeeper that negatively regulates SHH signal transduction by repressing the activation of target genes. Mice lacking this Gli3 "brake" die perinatally due to a variety of congenital malformations including digit polydactyly and severe CNS patterning defects. As this lethality has precluded the study of the functions of Gli3 during per- and postnatal development and adult life in more detail, we have generated a mouse model that allows to inactivate Gli3 in a temporally and/or spatially controlled manner either during embryogenesis or after birth. Using this so-called conditional Gli3 allele, we are now dissecting the functions and temporal requirement of this SHH gatekeeper during limb and brain development in mouse embryos and in SHH-dependent tumorigenesis after birth. Using a novel technique (RMCE), we have also generated additional alterations in the Gli3 locus, that allow us to detect and purify the GLI3 containing transcriptional complexes from intact embryonic and adult tissues. This systems biology-type approach in combination with cell-biochemistry aims to analyse of the functions and interactions of GLI3 during embryogenesis, tumourigenesis and in adult tissues and stem cells.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
The mouse limb bud is an excellent model to study how groups of cells organize themselves into structures. A key player is the transcriptional regulator GLI3, which functions first upstream of SHH in the polarisation of the limb field. Later, SHH regulate s GLI3 processing such that low levels of the transcriptional repressor (GLI3R) correlate with high levels of SHH signalling in the posterior limb bud. The resulting GLI3R gradient is essential for distal progression of limb development and specification of digit identities. My research will focus on the following main unsolved questions: the mechanism controlling Gli3 activation and thereby polarization of the limb field remains unknown together with the majority of direct GLI3 targets. Furthermore, in spite of proposals that GLI3 functions differ significantly during early -SHH independent- and subsequent -SHH dependent- limb bud development, the temporal modulation of GLI3 functions has not been studied. The specific objectives are:1) Identify the mechanism controlling Gli3 activation using a BAC transgenic approach with an in-frame fusion of a GFP tag (BAC-Gli3/gfp) combined with manipulation of candidate pathways/genes in cultured embryos and genetics.2) Identify direct transcriptional targets of Gli3 in the limb bud by FACS cell isolation and micro-arrays using the transgenic (1) and knock-in mouse strains (3).3) GLI3 roles will be dissected by tamoxifen-induced conditional inactivation of Gli3 at specific stages: before, during and after SHH signalling . These mice are a general model to analyse GLI3 roles during development and adult life (including stem cell renewal and carcinogenesis).My goal is to establish an independent research group that analyses bio-medically relevant aspects of developmental signals (e.g. Shh/Wnt) using mouse and fish models. Through the EIF I will gain competences in advanced mouse genetics, an expertise mastered in the host group, and complement my previous training.
Оригинален текст от CORDIS (на английски).
Участници
- UNIVERSITAET BASEL · BASELКоординаторШвейцария
Връзки
Данни: CORDIS, © Европейски съюз