Precision of Positional Information Along the Developing Cochlea Radial Axis: Linear BMP Activity Helps Set the Stage
Developing embryos rely on morphogenetic signals to inform cells about where they are in space and respond to their positions through the appropriate expression of fate-determining genes. Computational and theoretical analyses are powerful tools that have proven to enhance and inform experimental work in developmental biology. In the study of positional information, mechanistic ordinary and partial differential equations are able to test and suggest hypotheses for morphogen network evolution. Information theoretic interpretations of these profiles have also been proven to be valuable towards making predictions.
These approaches are reviewed and used here together to investigate the morphogenetic signals instructing pattern formation during the earliest phase of development in the cochlea. When the transcription factors SOX2 and pSMAD1/5/9 (two crucial carriers of positional information)
are quantified here for the first time, new observations, questions, and hypotheses emerge that have been out of reach otherwise. Perhaps most intriguingly is the identification of a linear pSMAD1/5/9 profile over a supermajority of the radial axis.
This linear profile is shown to ‘set the stage’ by creating a 1:1 map between position and signal concentration. Feasible mechanisms responsible for maintaining this profile are simulated to propose the existence of a yet-unidentified BMP sink on the medial edge and suggests a role for Follistatin interaction with BMP, which there are currently doubts around. This likewise sets thestage for new experimental and simulation work to home in on the network dynamics implemented by the cochlea to turn a diffusive morphogen system into a linear signal. While BMP sets the stage of the radial axis, adding SOX2 more precisely assigns cells their places for this opening act with its steep profile that reduces positional error. The transition into subsequent phases where cell fates are assigned relies dependently on the precision encoded in this first phase in order to create the cellular pattern required to enable the sense of hearing.
- Doctor of Philosophy
- Biomedical Engineering
- West Lafayette