p38a/Mapkapk2a signaling regulates tristetraprolin in the yolk syncytial layer: A role for mRNA degradation in the morphogenesis of a novel embryonic structure in vertebrate development
Gomez de la Torre Canny, Sol
Wagner, Daniel S.
Doctor of Philosophy
The yolk syncytial layer (YSL) is a novel embryonic structure that is unique to teleost fishes like the zebrafish. How existing genetic mechanisms can change to contribute to the generation of morphological novelties such as the YSL is a fundamental question of evolutionary biology. To address this question we examined the function of mapkapk2a (mk2a). Mk2a is required for YSL morphogenesis. To study the requirement of Mk2a signaling during embryogenesis, we analyzed the betty boop mutant (bbp). Bbp encodes Mk2a, the zebrafish homolog of mammalian MK2, a protein kinase activated by the p38 MAPK signaling pathway. bbp mutants display a striking lysis phenotype. bbp mutant embryos lose the expression of multiple YSL-specific genes. Thus, we examined the role of tristetraprolin (Ttp), a MK2 regulated mRNA-binding protein that promotes degradation of specific mRNA targets. Manipulation of the endogenous activity of Ttp showed that Ttp regulates the stability of YSL-specific mRNA molecules, most notably of mxtx2, which encodes for a zebrafish-specific transcription factor that activates a large proportion of YSL-specific genes. Specific activation of the Mk2a in the YSL inhibits Ttp activity in this cell layer, and prevents expression of Mxtx2 in other cells of the embryo. Expression of Mxtx2 or activation of the p38a /Mk2a pathway outside of the YSL results in dramatic defects in development. MK2 is not required for embryogenesis in mammals. Mutation of MK2 results in impaired inflammatory response and resistance to inflammatory diseases. The ability to manipulate the activity of the members of this conserved pathway in this novel context suggests that epiboly may be a useful platform to probe the molecular mechanism of TTP-dependent mRNA degradation that plays a crucial role in the regulation of the inflammatory response in mammals.