Publicação
Rere (Atrophin2) in the left-right coordination of somitogenesis
| Resumo: | One of the most striking features of the vertebrate body plan organization is its bilateral symmetry, most evident at the level of the vertebrae and skeletal muscles. During my PhD, I showed that Rere (Atrophin2)-deficient mouse embryos form asymmetrical somites in a temporally defined window. During the time period spanning the formation of somites 7 to 13 in Rere mutants, there is a lack of left-right coordination of the oscillatory behavior of the cyclic genes and of determination front regression. This results in the desynchronization of the segmentation cascade, leading to a delay of the clock oscillations and wavefront regression on the right side, in turn, resulting in a delay of somite formation from the right rostral PSM. The somite laterality defect in the mutant is controlled by the left-right signaling machinery. Rere mutants are similar to embryos deprived of retinoic acid (RA). I then showed that Rere controls RA signaling, which is required to maintain somite symmetry by buffering Fgf8 action in the left-right signaling pathway. Rere is recruited to the promoter of RA targets (e.g., RAR-beta) but does not bind to the RAR-RXR complex. Rere binds to the nuclear receptor NR2F2 (COUP-TF2), which is also recruited to the RAR-beta promoter. Asymmetrical expression of NR2F2 in the PSM overlaps with the asymmetry of the RA signaling response, supporting a role for NR2F2 in the control of somite symmetry downstream of Rere and RA. Rere is also implicated in other RA-dependent processes, like myogenesis, supporting a more widespread function of Rere in RA signaling. By mass spectrometry, we identified Rereassociated proteins that will lead us to better comprehend RA signaling and the left-right coordination of somitogenesis. In humans, major defects of the bilateral symmetry of somite derivatives are observed at the spine level in a class of diseases called scoliosis. A better understanding of the Rere dependent, RA pathway described in this work, which affects the symmetry of vertebral precursors, could be clinically relevant to human spine pathologies. |
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| Autores principais: | Neto, Gonçalo Cadete Vilhais, 1978- |
| Assunto: | Vertebrados Somitogénese Ácido retinóico Rere Miogénese Espectrometria de massa Biologia do desenvolvimento Teses de doutoramento |
| Ano: | 2009 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso restrito |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | One of the most striking features of the vertebrate body plan organization is its bilateral symmetry, most evident at the level of the vertebrae and skeletal muscles. During my PhD, I showed that Rere (Atrophin2)-deficient mouse embryos form asymmetrical somites in a temporally defined window. During the time period spanning the formation of somites 7 to 13 in Rere mutants, there is a lack of left-right coordination of the oscillatory behavior of the cyclic genes and of determination front regression. This results in the desynchronization of the segmentation cascade, leading to a delay of the clock oscillations and wavefront regression on the right side, in turn, resulting in a delay of somite formation from the right rostral PSM. The somite laterality defect in the mutant is controlled by the left-right signaling machinery. Rere mutants are similar to embryos deprived of retinoic acid (RA). I then showed that Rere controls RA signaling, which is required to maintain somite symmetry by buffering Fgf8 action in the left-right signaling pathway. Rere is recruited to the promoter of RA targets (e.g., RAR-beta) but does not bind to the RAR-RXR complex. Rere binds to the nuclear receptor NR2F2 (COUP-TF2), which is also recruited to the RAR-beta promoter. Asymmetrical expression of NR2F2 in the PSM overlaps with the asymmetry of the RA signaling response, supporting a role for NR2F2 in the control of somite symmetry downstream of Rere and RA. Rere is also implicated in other RA-dependent processes, like myogenesis, supporting a more widespread function of Rere in RA signaling. By mass spectrometry, we identified Rereassociated proteins that will lead us to better comprehend RA signaling and the left-right coordination of somitogenesis. In humans, major defects of the bilateral symmetry of somite derivatives are observed at the spine level in a class of diseases called scoliosis. A better understanding of the Rere dependent, RA pathway described in this work, which affects the symmetry of vertebral precursors, could be clinically relevant to human spine pathologies. |
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