During neural development proliferating cells in the ventricular zone undergo repeated self-renewal to maintain the progenitor pool or, alternatively exit the cell cycle and differentiate into neurons. This process is regulated by the coordination of cell intrinsic signals and regional and temporal specific external cues which determine the type and the amount of neurons generated. After a neural progenitor has committed to differentiation the process of balancing internal and external signals continues during maturation to guide the initiation, elongation and branching of the axon. One major remaining question is how biological regulation can be integrated with the developmental context to produce a specific outcome. Here, I show that microRNAs and particularly, microRNA-9 (miR-9) plays a very important role in vertebrate neural development; a role, which is highly dependent on the context. In X. tropicalis, miR-9 reveals regional specific progenitor heterogeneity - it is required for cell cycle exit and differentiation throughout the neural tube, but forebrain progenitors additionally, and uniquely, require miR-9 for their survival. I have shown that the major miR-9 target in this context is the hairy and enhancer of split gene hairy1. When miR-9 is absent, hairy1 domain expands and selectively activates different signaling pathways in the forebrain and the hindbrain, culminating in the regional specific differences we observed.In the mouse, the homologue of hairy1 - Hes1 expression is oscillatory which is essential for progenitor maintenance. I have shown that Hes1 is also a subject of miR-9 regulation, which, in this context, is necessary for maintaining the oscillations. Furthermore, miR-9 is also regulated by Hes1, which leads to opposite-phase oscillations of miR-9 primary transcripts, but step-wise accumulation of the mature miR-9 form due to its stability. I propose that miR-9 levels act as output to measure the number of Hes1 cycles and at certain critical threshold levels this leads to dampening of the oscillations and allows progenitors to differentiate.MiR-9 is also expressed in differentiated neurons in the forebrain, where its function is completely unknown. We have shown that in this context it promotes axon branching and inhibits axon growth through the microtubule-associated protein 1B (MAP1B). We have also provided evidence that brain-derived neurotrophic factor (BDNF) can modulate this process by regulating miR-9 levels in the axon. Overall, these findings contribute to our understanding of neural development and provide novel explanation of how to cell fate decisions are integrated with context-specific signals to generate a specific outcome.
|Date of Award||1 Aug 2012|
- The University of Manchester
|Supervisor||Nancy Papalopulu (Supervisor)|