Redefining the morphogen hypothesis: BMP-FGF interactions and kinetics in the developing telencephalon

Neural development is a highly orchestrated process, patterning of naïve tissue into highly evolved structures with multiple cell types and functions is highly complex and not fully understood. Conventional understanding of pattern formation assumes extrinsic morphogen concentration to be the sole determining factor. However, this perspective has been challenged recently, raising the possibility of additional mechanisms at play.In this dissertation, I address the process of patterning and neurodevelopment by first understanding the morphogens involved in patterning the developing telencephalon and their interactions, and secondly by studying the kinetics and signaling pathway of these morphogens and how they implicate patterning and border formation.My studies demonstrated that BMP and FGF signaling pathways interact in a mutually inhibitory fashion at both the population level and single cell level. Ixviidetermined that BMP signaling exhibited fast activation and slow deactivation kinetics, whereas FGF signaling displayed slow acting kinetics. Based on these findings, I determined the advantages of such network design in tissue patterning and robust border formation. I demonstrated that patterning is a dynamic process that occurs over time. I introduced the notion of temporal integration in patterning the developing telencephalon, challenging the canonical morphogen theory, which states that gene expression and cell fate decisions are based on morphogen concentration alone. Lastly, I discovered that a slow and integrative system is robust to perturbations, where a transient disruption of signaling leads to developmental delay with eventual catch up recovery.Taken together, my findings have defined the interaction between BMPs and FGFs in the developing telencephalon, demonstrated the advantages of different signaling kinetics, and presented a novel mode of interaction between morphogens that is likely to be a general phenomenon. I have demonstrated the importance of studying patterning as a dynamic process, demonstrating the importance of temporal integration, thereby redefining the current understanding of patterning of naïve tissues by morphogens