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Rere (Atrophin2) in the left-right coordination of somitogenesis
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Resumo(s)
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.
Resumo alargado em portuguê disponível no documento
Resumo alargado em portuguê disponível no documento
Descrição
Tese de doutoramento, Biologia (Biologia do Desenvolvimento), 2009, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Vertebrados Somitogénese Ácido retinóico Rere Miogénese Espectrometria de massa Biologia do desenvolvimento Teses de doutoramento