Retinoic acid signaling regulation and its contribution to robust, precise, and complex zebrafish hindbrain development.

摘要

Development is an orchestrated series of molecular interactions, each of which must occur in the right place, at the correct time, and of a particular amplitude. In order for each of these interactions to fulfill their necessary function, they must be regulated. This regulation is required so that development of the organism is robust to variation, precise in determining cell fates, and ultimately produces a complex, patterned organism. Development uses many different mechanisms for achieving the correct regulation of each step in each pathway. To begin to understand some of these mechanisms, we have studied the retinoic acid signaling pathway and how it is regulated in patterning the zebrafish hindbrain.;Retinoic acid (RA) is a unique signaling molecule due to its synthesis from the dietary precursor vitamin A, and either too much or too little vitamin A leads to developmental defects. Despite this, retinoic acid is used in multiple ways during embryonic development over a large, but finite, concentration range. This suggests that synthesis, signaling, and degradation of retinoic acid must be regulated in such a way to account for differences in vitamin A availability. In my thesis, I investigate mechanisms by which RA is regulated during development. Facilitated transport of RA by cellular retinoic acid binding proteins (Crabps) is one mechanism that maintains robust hindbrain patterning despite variation in RA concentration. Noise in intracellular RA, due to small variations in synthesis, diffusion and degradation, combined with noise from transcription and translation of RA target genes, provides a mechanism for cell fate reversibility, which drives precise gene expression boundaries. RA is known to induce many cell fate decisions, and one potential mechanism that explains that ability is RA activation of two different receptor sub-types, leading to complex cell fates from a single signaling molecule. When examined as a whole, my thesis work provides insight into diverse mechanisms that regulate RA to achieve robust, precise, and complex development.