Mechanism of development regulation of brain size

How does a brain reach its correct size and form? What molecular mechanisms control brain size and how is growth coordinated between different brain regions? Specific signaling molecules are implicated in the expansion of progenitor subsets along the neural axis, yet little is known about the molecular mechanisms that coordinate growth over different brain regions. This thesis explores the idea that the ventricular system acts as a 'simplistic circulatory system' during development to coordinate the growth of distant brain regions. I hypothesized that the primary cilia of ventricular-lining proliferative cells act as sensors to allow the developing brain to detect and---in a coordinated fashion---to respond to changing developmental cues sent through the cerebral spinal fluid (CSF).; I examined the role of the primary cilium as an environmental sensor in growth regulation of the cerebral cortex. Here, I show that primary cilia are necessary for the normal growth regulation of the cerebral cortex and Gli3 processing. I demonstrate that loss of Kif3a, a component of functional primary cilia, leads to primary cilia degeneration, a marked overgrowth of the cortex, and alteration of cell cycle kinetics within cortical progenitors. The G1 phase of the cell cycle is shortened by reduced processing of Gli3 from its activator to its repressor form and subsequent increased expression of cyclin D1 and Fgf15. Gli3 processing defects accelerate cell cycle kinetics and cause the molecular changes seen in brains lacking cilia. Lastly, I show that Gli3 processing and cyclin D1 levels are tightly regulated during normal development and correlate with changes in the length of the cell cycle of cortical progenitors. Together these data suggest a model whereby primary cilia control the growth of the cerebral cortex through cell cycle regulation and likely serve similar roles in different brain regions to coordinate growth over a complex organ such as the brain.