BACKGROUND: Only a handful of signaling pathways are major actors of development and responsible for both the conservation and the diversification of animal morphologies. To explain this twofold nature, gene duplication and enhancer evolution were predominantly put forth as tinkering mechanisms whereas the evolution of alternative isoforms has been, so far, overlooked. We investigate here the role of gain and loss of isoforms using @entity58643 , a gene of the Ecodysplasin pathway, implicated in morphological evolution. A previous study had suggested a scenario of @entity1017 and loss with an alternative isoform (A) newly gained in mammals but secondarily lost in @entity19 lineage. RESULTS: For a comprehensive view of A and B @entity58643 isoforms history during @entity1 evolution, we obtained sequences for both isoforms in representative mammals and performed in vitro translations to support functional predictions. We showed that the ancestral B isoform is well conserved, whereas the @entity1 -specific A isoform was lost at least 7 times independently in terminal lineages throughout @entity1 phylogeny. Then, to gain insights into the functional relevance of this evolutionary pattern, we compared the biological function of these isoforms: i) In cellulo promoter assays showed that they are transcribed from two alternative promoters, only B exhibiting feedback regulation. ii) RT-PCR in various tissues and ENCODE data suggested that B isoform is systematically expressed whereas A isoform showed a more tissue-specific expression. iii) Both isoforms activated the NF-kB pathway in an in cellulo reporter assay, albeit at different levels and with different dynamics since A isoform exhibited feedback regulation at the protein level. Finally, only B isoform could rescue a @entity3392 @entity69538 knockdown. CONCLUSIONS: These results suggest that the newly evolved A isoform enables modulating @entity22577 signaling in specific conditions and with different dynamics. We speculate that during @entity1 diversification, A isoform regulation may have evolved rapidly, accompanying and possibly supporting the diversity of ectodermal appendages, while B isoform may have ensured essential roles. This study makes the case to pay greater attention to mosaic loss of evolutionarily speaking "young" isoforms as an important mechanism underlying phenotypic diversity and not simply as a manifestation of neutral evolution.

Tinkering signaling pathways by gain and loss of protein isoforms: the case of the XXXX pathway regulator @entity58643 .

@entity1 :: ('9606', 'Species') :: ['mammal'] @entity69538 :: ('566761(Tax:7955)', 'Gene') :: ['edaradd'] @entity58643 :: ('128178', 'Gene') :: ['Edaradd'] @entity19 :: ('10090', 'Species') :: ['mouse'] @entity1017 :: ('MESH:D015430', 'Disease') :: ['isoform gain'] @entity22577 :: ('1896', 'Gene') :: ['EDA'] @entity3392 :: ('7955', 'Species') :: ['zebrafish']
@entity22577 :: (1896,Gene) :: ['EDA']
